Benzodioxole derivatives

ABSTRACT

A new benzodioxole derivative has a substituent in the phenyl ring which is a carboxyalkylthioalkyl or the like and is effective to treat a liver disease.

This application is a divisional of application Ser. No. 07/832,220,filed on Feb. 6, 1992, U.S. Pat. No. 5,292,901, which is a divisionalapplication under 37 CFR 1.60 of Ser. No. 07/517,444, filed on Apr. 23,1990, U.S. Pat. No. 5,110,956, which is a continuation application under37 CFR 1.62 of Ser. No. 07/160,333, filed on Feb. 25, 1988 abandoned.

The invention relates to a benzodioxole derivative, a pharmacologicallyacceptable salt thereof, a pharmaceutical composition containing thesame, a process for preparing the same and the medical treatment ofliver troubles therewith. The invention compound exhibits an excellentactivity as a medicine for liver troubles such as liver diseases of thehuman being and liver injury of animals.

STATEMENT OF PRIOR ARTS

The development of a liver trouble remedy is very difficult, because thecause, figure and pathophysiology of liver troubles are various andmostly unobvious.

Representative medicines which are widely used in the treatment andprevention of liver troubles and evaluated to be clinically effectiveinclude glycyrrhizin preparations. Although the glycyrrhizinpreparations are generally believed to be effective in the treatment ofa liver affection, cirrhosis and hepatitis and in the protection of aliver after a surgical operation, however, none of the preparationsexhibit a sufficient effect and they are further problematic in thatthey cause a steroidal adverse reaction. Further, the glycyrrhizinpreparations are disadvantages in that the oral administration thereofis ineffective, though they can be administered as intravenousinjections to give an effect.

Under these circumstances, it is strongly desired to develop anexcellent medicine which is excellent in safety and can be orallyadministered to exhibit an excellent effect.

Under these circumstances, the inventors of the present invention haveeagerly studied to develop a new liver trouble remedy.

The inventors of the present invention have long studied plants whichhave been used as fold medicines and have found2-[(phenylmethyl)trithio]ethanol (A) and cubebin (B) which arerepresented by the general formulas: ##STR1## and are active compoundseffective as liver trouble remedies, from Petiveria alliacea L. andCinnamonum porrectum (Roxb.) Kosterm.

Thereafter, the inventors of the present invention have synthesizedvarious compounds by using the above compounds as basic compounds andhave examined the obtained compounds for pharmacological activity. As aresult of the examination, they have found that benzodioxole derivativesrepresented by the general formula (I) or pharmacologically acceptablesalts thereof exhibit higher safety and are useful as a more excellentliver trouble remedy. The present invention has been accomplished on thebasis of this finding.

The following two patent publications show liver trouble remedies whichare different from the benzodioxole derivatives of the present inventionin chemical structure.

More precisely, the compounds disclosed in Japanese Patent Laid-Open No.29522/1987 have each a structure comprising a benzodioxole ring and asaturated alkyl group bonded to the phenyl ring of the benzodioxole ringand most of them have already been known.

Further, Japanese Patent Laid-Open No. 39583/1987 discloses(1,3-benzodioxol-5-yl)methylthio derivatives. However, the group bondedto the S atom of these derivatives is a heterocyclic group such aspyridine, pyrimidine or thiadiazole, so that the derivatives are clearlydifferent from the compounds of the present invention in structure.

As described above, the present invention has been accomplished on thebasis of a hint taken from the compounds (A) and (B) found by theinventors of the present invention themselves from plant components andtherefore is different from the inventions of the above two Laid-Open,Patents in conception. Accordingly, the compounds of the presentinvention are different from those of the above two Laid-Open Patents inchemical structure.

SUMMARY OF THE INVENTION

The invention provides a novel benzodioxole derivative having theformula (I) and a pharmacologically acceptable salt thereof: ##STR2## inwhich T, U, V and W are each defined according to the below shownrespective six groups (a) to (f):

(a) T is hydrogen, U is hydrogen, V is R3 and W is ##STR3## wherein R¹and R² may be the same or different from each other and each representsa hydrogen atom or an alkyl, arylalkyl or heteroarylalkyl group, R³represents a hydrogen atom or a lower alkyl, arylalkyl orheteroarylalkyl group, R⁴ represents a hydrogen atom or a lower alkylgroup, or R² and R³ may form together an at least 4-membered ring and Xrepresents a group of the formula: ##STR4## with the proviso that R¹ isan alkyl, arylalkyl or heteroarylalkyl group having at least 3 carbonatoms when X is a --S-- group and R³ and R² are each a hydrogen atom;

(b) T is hydrogen, U is hydrogen, V is hydrogen and W is --(CH₂)₂ --X--R

wherein X represents a group of the formula: ##STR5##

R represents:

(1) a hydrogen atom or a lower alkyl group,

(2) a group of the formula: --(CH₂)_(n) --COOR¹ in which n represents aninteger of 1 to 5 and R¹ represents a hydrogen atom or a lower alkylgroup,

(3) a group of the formula: --(CH₂)_(n) --OR² in which n represents aninteger of 1 to 5 and R² represents a hydrogen atom, a lower alkyl groupor an acyl group,

(4) a group of the formula: ##STR6## in which n represents an integer of1 to 5, and R³ and R⁴, which may be the same or different from eachother, each represent a hydrogen atom, a lower alkyl or carboxymethylgroup,

(5) a group of the formula: ##STR7## in which n represents an integer of1 to 5, and R⁵ and R⁶, which may be the same or different from eachother, each represents a hydrogen atom or a lower alkyl group,

(6) a group of the formula: ##STR8## in which n represents an integer of1 to 5 and R⁷ represents a hydrogen atom or a lower alkyl group,

(b 7) a group of the formula shown in the above item (2) but wherein oneor more carbon atoms of the alkylene chain having n carbon atoms arebonded with a lower alkyl group or a group of the formula: --COOR⁸ inwhich R⁸ represents a hydrogen atom or a lower alkyl group, in place ofhydrogen atom,

(8) a group of the formula shown in the above item (3) but wherein oneor more carbon atoms of the alkylene chain having n carbon atoms arebonded with a hydroxyl group in place of hydrogen atom, or

(9) a group of the formula: ##STR9## in which n represents an integer of1 to 5 and m represents an integer of 3 or 4,

with the proviso that when X represents a group of the formula: --S--and R represents a lower alkyl group, the lower alkyl group cannot be amethyl group;

(c) T is hydrogen, U is hydrogen, V is R1 and W is ##STR10## wherein R¹represents a hydrogen atom or a lower alkyl or lower alkoxy-lower alkylgroup, R² represents a hydrogen atom or a lower alkyl or lower alkoxygroup, R³ represents a hydrogen atom or a lower alkyl group and R⁴represents a hydrogen atom or a lower alkyl group, or R¹ and R² or R¹and R³ may form together a 5- to 7-membered ring, with the proviso thatall of R¹, R² and R³ cannot be hydrogen atoms at the same time;

(d) T is R4, U is R5, V is R3 and W is ##STR11## wherein R¹ and R² maybe the same or different from each other and each represents a hydrogenatom or a lower alkyl group,

R³ represents a hydrogen atom, a lower alkyl group or a group of theformula: --(CH₂)_(n) COOH in which n represents an integer of 1 to 3,

R⁴ and R⁵ may be the same or different from each other and eachrepresents a hydrogen atom or a lower alkyl group, X represents a groupof the formula: ##STR12##

A represents a lower alkyl group, a group of the formula: --(CH₂)_(n')-Het in which n' represents an integer of 1 to 3 and Het represents asubstituted or unsubstituted heterocyclic ring, a group of the formula:##STR13## a group of the formula: ##STR14## a group of the formula:##STR15## in which R⁶ and R⁷ may be the same or different from eachother and each represents a hydrogen atom or a lower alkyl group, agroup of the formula: --CH₂ --CN, a group of the formula: ##STR16## inwhich R⁸ represents a lower alkyl group or a group of the formula:##STR17## in which p represents an integer of 1 to 3 and R⁹ and R¹⁰ maybe the same or different from each other and each represents a loweralkyl group;

(e) T is hydrogen, U is hydrogen, V is hydrogen and W is ##STR18##wherein X is a group of the formula: --CH₂ --, --CH₂ --CH₂ --, --CH₂--CH₂ --CH₂ -- or ##STR19## R¹ is a hydrogen atom or a lower alkyl groupand Y is hydrogen atom or an alkyl, hydroxyl, carboxyl, aryl orheteroarylcarbonyloxy group; and

(f) T is hydrogen, U is hydrogen, V is R3 and W is ##STR20## wherein R¹and R² may be the same or different from each other and each representsa hydrogen atom or a lower alkyl, aryl or arylalkyl group;

n represents an integer of 0 or 1;

Y represents a group of the formula:

--COOH or ##STR21## wherein R4 and R5 may be the same as or differentfrom each other and each represents a hydrogen atom or a lower alkyl orcarboxymethyl group and R³ represents a hydrogen atom or a lower alkylor arylalkyl group.

In addition, the invention provides a process for preparing the aboveshown benzodioxole derivative and a pharmaceutical compositioncontaining it and a pharmacologically acceptable carrier.

The invention compound (I) consists of six compound groups (I-a), (I-b),(I-c), (I-d), (I-e) and (I-f). Each group is defined below,corresponding to the six group definitions (a), (b), (c), (d), (e) and(f) of T, U, V and W of the formula (I), respectively.

Compound Group (I-a)

The compound group (I-a) has the formula (I-a): ##STR22## wherein R¹ andR² may be the same or different from each other and each represents ahydrogen atom or an alkyl, arylalkyl or heteroarylalkyl group, R³represents a hydrogen atom or a lower alkyl, arylalkyl orheteroarylalkyl group, R⁴ represents a hydrogen atom or a lower alkylgroup, or R² and R³ may form together an at least 4-membered ring and Xrepresents a group of the formula: ##STR23## with the proviso that R¹ isan alkyl, arylalkyl or heteroarylalkyl group having at least 3 carbonatoms when X is a --S-- group and R³ and R² are each a hydrogen atom.

In the formula (I-a), the alkyl for R1 and R2 includes a straight orbranched alkyl, such as methyl, ethyl, n-propyl, n-butyl, iso-propyl,iso-butyl, 1-methylpropyl, tert-butyl, n-pentyl, 1-ethylpropyl, isoamyl,n-hexyl, n-heptyl, n-octyl, n-nonyl and n-decyl. Methyl, ethyl,n-propyl, iso-propyl and n-butyl are preferable. The lower for R3 and R4includes a straight or branched alkyl having 1 to 6 carbon atoms, suchas methyl, ethyl, n-propyl, n-butyl, iso-propyl, iso-butyl,1-methylpropyl, tert-butyl, n-pentyl, 1-ethylpropyl, iso-amyl andn-hexyl. Methyl, ethyl and n-propyl are preferable. The arylalkyl forR1, R2 and R3 includes benzyl and phenethyl. The hetero-arylalkyl forthe same includes a heterocyclic ring connected with an alkyl such asmethyl, ethyl and propyl. The heteroaryl includes a five- orsix-membered ring having nitrogen such as pyridine, pyrimidine, pyrrole,pyrazole and imidazole, thiazole, oxazole and furane. A preferablehetero-arylalkyl is pyridylmethyl, pyrimidylmethyl or furylmethyl, thealkyl being connected with the hetero-cyclic ring at any position. R2and R3 may form a 4- or more membered cyclic ring together incombination. This is supported by Examples 15 and 17.

Compound Group (I-b)

The compound group (I-b) has the formula (I-b): ##STR24## wherein Xrepresents a group of the formula: ##STR25## and

R represents:

(1) a hydrogen atom or a lower alkyl group,

(2) a group of the formula: --(CH₂)_(n) --COOR¹ in which n represents aninteger of 1 to 5 and R¹ represents a hydrogen atom or a lower alkylgroup,

(3) a group of the formula: --(CH₂)_(n) --OR² in which n represents aninteger of 1 to 5 and R² represents a hydrogen atom, a lower alkyl groupor an acyl group,

(4) a group of the formula: ##STR26## in which n represents an integerof 1 to 5, and R³ and R⁴, which may be the same or different from eachother, each represents a hydrogen atom, a lower alkyl or carboxymethylgroup,

(5) a group of the formula: ##STR27## in which n represents an integerof 1 to 5, and R⁵ and R⁶, which may be the same or different from eachother, each represents an hydrogen atom or a lower alkyl group,

(6) a group of the formula: ##STR28## in which n represents an integerof 1 to 5 and R⁷ represents a hydrogen atom or a lower alkyl group,

(7) a group of the formula shown in the above item (2) but wherein oneor more carbon atoms of the alkylene chain having n carbon atoms arebonded with a lower alkyl group or a group of the formula: --COOR⁸ inwhich R⁸ represents a hydrogen atom or a lower alkyl group, in place ofhydrogen atom,

(8) a group of the formula shown in the above item (3) but wherein oneor more carbon atoms of the alkylene chain having n carbon atoms arebonded with a hydroxyl group in place of hydrogen atom, or

(9) a group of the formula: ##STR29##

in which n represents an integer of 1 to 5 and m represents an integerof 3 or 4,

with the proviso that when X represents a group of the formula: --S--and R represents a lower alkyl group, the lower alkyl group cannot be amethyl group.

In the formula (I-b), the lower alkyl for R1, R2, R3, R4, R5, R6, R7 andR8 includes a straight or branched alkyl having 1 to 6 carbon atoms suchas methyl, ethyl, n-propyl, n-butyl, iso-propyl, iso-butyl,1-methylpropyl, tert-butyl, n-pentyl, 1-ethylpropyl, iso-amyl andn-hexyl. Methyl and ethyl are preferable. The acyl for R2 includes aresidue of an organic acid such as an aliphatic saturated carboxylicacid, an aliphatic unsaturated carboxylic acid, a carboxylic caroxylicacid and a hetero-cyclic carboxylic acid. It includes in particular alower alkanoyl such as formyl, acetyl, propionyl, butyryl, iso-butyryl,valeryl, iso-valeryl and pivaloyl, an aroyl such as benzoyl, toluoyl andnaphthoyl and a hetro-aroyl such as furoyl, nicotinoyl andiso-nicotinoyl.

Compound Group (I-c)

The compound group (I-c) has the formula (I-c): ##STR30## wherein R¹represents a hydrogen atom or a lower alkyl or lower alkoxy-lower alkylgroup, R² represents a hydrogen atom or a lower alkyl or lower alkoxygroup, R³ represents a hydrogen atom or a lower alkyl group and R⁴represents a hydrogen atom or a lower alkyl group, or R¹ and R² or R¹and R³ may form together a 5- to 7-membered ring, with the proviso thatall of R¹, R² and R³ cannot be hydrogen atoms at the same time.

In the formula (I-c), the lower alkyl for R1, R2, R3 and R4 includes analkyl, straight or branched, having 1 to 6 carbon atoms, such as methyl,ethyl, propyl, iso-propyl, butyl, iso-butyl, sec-butyl, tert-butyl,pentyl (amyl), iso-pentyl, neopentyl, tert-pentyl, 1-methylbutyl,2-methylbutyl, 1,2-dimethylpropyl, hexyl, iso-hexyl, 1-methylpentyl,2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl,2,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl,3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1,1,2-trimethylpropyl,1,2,2-trimethylpropyl, 1-ethyl-1-methylpropyl and1-ethyl-2-methylpropyl. Methyl, ethyl, propyl and iso-propyl arepreferable. The lower alkoxy for R2 includes an alkoxy, straight orbranched, having 1 to 6 carbon atoms, such as methoxy, ethoxy,n-propoxy, iso-propoxy, n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy,pentyloxy, iso-pentyloxy, neopentyloxy, tert-pentyloxy, 1-methylbutoxy,2-methylbutoxy, 1,2-dimethylpropoxy and hexyloxy. Methoxy and ethoxy arepreferable. The lower alkoxy-lower alkyl for R1 includes methoxymethyl,methoxyethyl, methoxypropyl, ethoxymethyl, ethoxyethyl, ethoxypropyl,propoxymethyl, propoxyethyl and propoxypropyl. Methoxymethyl andethoxymethyl are preferable. R1 and R2 may, together in combination,form a 5- to 7-membered ring. This is exemplified in Example 13. The 5-to 7-membered ring may contain oxygen atom, in addition to a ringconsisting of carbon atoms. R1 and R3 also may, together in combination,form a 5- to 7-membered ring, exemplified in Example 11.

Compound Group (I-d)

The compound group (I-d) has the formula (I-d): ##STR31## wherein R¹ andR² may be the same or different from each other and each represents ahydrogen atom or a lower alkyl group,

R³ represents a hydrogen atom, a lower alkyl group or a group of theformula: --(CH₂)_(n) COOH in which n represents an integer of 1 to 3,

R⁴ and R⁵ may be the same or different from each other and eachrepresents a hydrogen atom or a lower alkyl group, X represents a groupof the formula: ##STR32##

A represents a lower alkyl group, a group of the formula: --(CH₂)_(n')-Het in which n' represents an integer of 1 to 3 and Het represents asubstituted or unsubstituted heterocyclic ring, a group of the formula:##STR33## a group of the formula: ##STR34## a group of the formula:##STR35## in which R⁶ and R⁷ may be the same or different from eachother and each represents a hydrogen atom or a lower alkyl group, agroup of the formula: --CH₂ --CN, a group of the formula: ##STR36## inwhich R⁸ represents a lower alkyl group or a group of the formula:##STR37## in which p represents an integer of 1 to 3 and R⁹ and R¹⁰ maybe the same or different from each other and each represents a loweralkyl group.

In the formula (I-d), the lower alkyl for R1, R2, R3, R4, R5, R6, R7,R8, R9 and R10 includes a straight or branched alkyl having 1 to 6carbon atoms such as methyl, ethyl, propyl, iso-propyl, butyl,iso-butyl, sec-butyl, tert-butyl, pentyl (amyl), iso-pentyl, neopentyl,tert-pentyl, 1-methylbutyl, 2-methylbutyl, 1,2-dimethylpropyl, hexyl,iso-hexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl,1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl,1,3-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl,2-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl,1-ethyl-1-methylpropyl and 1-ethyl-2-methylpropyl. Methyl, ethyl, propyland iso-propyl are preferable. The hetero-cyclic ring, called Het in theA, means a nitrogen-containing hetero-cyclic ring, such as pyridine,pyradine, pyrimidine, imidazole, pyrazole, oxazole, iso-oxazole,thiazole and iso-thiazole. The hetero-cyclic ring may have a substituentsuch as a lower alkyl, for example methyl, and hydroxyl. Pyridyl,imidazolyl and iso-oxazolyl are preferable.

Compound Group (I-e)

The compound group (I-e) has the formula (I-e): ##STR38## wherein X is agroup of the formula: --CH₂ --, --CH₂ --CH₂ --, --CH₂ --CH₂ --CH₂ -- or##STR39## R¹ is a hydrogen atom or a lower alkyl group and Y is hydrogenatom or an alkyl, hydroxyl, carboxyl, aryl or heteroarylcarbonyloxygroup.

In the formula (I-e), the lower alkyl for R1 includes an alkyl having 1to 6 carbon atoms, straight or branched, such as methyl, ethyl,n-propyl, n-butyl, iso-propyl, iso-butyl, 1-methylpropyl, tert-butyl,n-pentyl, 1-ethylpropyl, iso-amyl and n-hexyl. Methyl, ethyl andn-propyl are preferable. The alkyl for Y includes an alkyl, straight orbranched, such as methyl, ethyl, n-propyl, n-butyl, iso-propyl,iso-butyl, 1-methylpropyl, tert-butyl, n-pentyl, 1-ethylpropyl,iso-amyl, n-hexyl, n-heptyl, n-octyl, n-nonyl and n-decyl. The aryl forR1 includes phenyl, tolyl, xylyl, biphenyl and naphthyl. Phenyl ispreferable. The hetero-arylcarboxyloxy includes one derived from anitrogen-containing, 5- or 6-membered cyclic ring such as pyridine,pyrimidine, pyrrole, pyrazole and imidazole, thiazole, oxazole orfurane. Nicotinoyloxy is preferable.

Compound Group (I-f)

The compound group (I-f) has the formula (I-f): ##STR40## wherein R¹ andR² may be the same or different from each other and each represents ahydrogen atom or a lower alkyl, aryl or arylalkyl group; n represents aninteger of 0 or 1; Y represents a group of the formula: --COOH or##STR41## (wherein R⁴ and R⁵ may be the or different from each other andeach represents a hydrogen atom or a lower alkyl or carboxymethyl group)and R³ represents a hydrogen atom or a lower alkyl or arylalkyl group.

The lower alkyl group in the above definition with respect to the groupsR¹, R², R³, R⁴ and R⁵ of the compound (I) according to the presentinvention is a straight-chain or branched alkyl group having 1 to 6carbon atoms and examples thereof include methyl, ethyl, n-propyl,n-butyl, isopropyl, isobutyl, 1-methylpropyl, tert-butyl, n-pentyl,1-ethylpropyl, isoamyl and n-hexyl groups.

The aryl group in the definition with respect to the groups R¹ and R²includes phenyl, toyl and naphthyl groups, among which phenyl group ismost preferred.

Preferred examples of the arylalkyl group in the definition with respectto the groups R¹, R² and R³ include groups derived from the above arylgroups, among which benzyl and phenethyl groups are most preferred.

In the compounds according to the invention, those having the formulae(I-a), (I-b) and (I-f), respectively, are preferable.

In the invention, a preferable group of the compounds has the formula(I) in which T is hydrogen, U is hydrogen, V is R3 and W is (a) or (f),in which R3, (a) and (f) are defined above, provided that the definitionof (f) excludes the cases where n is zero, Y is --COOH, R1 and R2 areeach hydrogen, a lower alkyl or an arylalkyl and R3 is hydrogen, a loweralkyl or an arylalkyl.

It is more preferable in the formula (I-a) that X is --S--, R3 ishydrogen or a lower alkyl and R1 and R2 are each hydrogen or a loweralkyl. The compound having the formula (I-a) in which R3 is hydrogen, R1is hydrogen, R2 is n-propyl, X is --S-- and R4 is hydrogen and sodiumsalt thereof are most preferable.

Also the compound having the formula (I-f) in which R3 is hydrogen, R1and R2 are hydrogen, n is one and Y is --COOH and sodium salt thereofare most preferable.

In the formula (I-b), X is preferred to be --S--. When this is the case,R is preferred to be --CH2--COOH, --(CH2)n--CH(NH2)--COOR7 or --CH₂--CH(NH₂)COOH. In addition, it is preferred that X is --S--, R3 ishydrogen, R1 is hydrogen and R2 is --C3H8; X is --S--, R3 is hydrogen,R1 is --CH3 and R2 is --CH3; or X is --S--, R3 is --CH3 or --C2H5, R1 ishydrogen and R2 is --C2H5.

All the compounds employed in the pharmacological tests, shown below,are more important to the invention. In particular, the compounds 1 to 5shown in Table 1 in view of the the compound group (I-a) and thecompounds 1, 2, 4, 7, 8, 10, 11, 12, 13 and 15 listed in Table 6 in viewof the compound group (I-f) are most preferred.

The pharmacologically acceptable salts may be ordinary non-toxic saltsand examples thereof include salts of alkali metals such as sodium andpotassium; salts of alkaline earth metals such as calcium and magnesium;salts of organic amines such as trimethylamine, triethylamine, pyridine,picoline, dicyclohexylamine and N,N'-dibenzylethylenediamine andammonium salts and additionally, depending upon the substituent,inorganic acid salts such as hydrochloride, hydrobromide, sulfate andphosphate; organic acid salts such as acetate, maleate, tartrate,methanesulfonate, benzenesulfonate and toluenesulfonate and salts ofamino acids such as arginine and aspartic and glutamic acids. Further,these salts may form hydrates.

Although the compounds of the present invention may have an asymmetriccarbon atom depending upon the substituents to be present as opticalisomers, it is a matter of course that these isomers are included in thescope of the present invention.

It should be understood from the results of Experimental Examples 1 and2 that the compounds of the present invention remarkably inhibit theliver trouble due to D-galactosamine or carbon tetrachloride. Thus, thecompounds of the present invention are very useful as liver troubleremedies.

Accordingly, the compounds of the present invention are useful as atherapeutic and preventive medicine for various liver troubles ofanimals including human beings. More precisely, they can be used in thetreatment and prevention of chronic or acute hepatitis, liver affectiondue to drug, viral hepatitis, alcoholic hepatitis and choloplania andeven cirrhosis as a terminal symptom of these diseases.

Further, it should be understood from the results of ExperimentalExample 3 that the compounds of the present invention exhibit aremarkably low toxicity and are excellent in safety. Therefore, thecompounds of the present invention are highly valuable in this regard,because they are generally administered repeatedly for a prolongedperiod of time owing to the nature of the trouble.

When the compounds of the present invention are administered as atherapeutic and preventive medicine for liver troubles, they may beorally administered as a powder, granule, capsule, syrup or the like ormay be parenterally administered as a suppository, injection, externalpreparation of drop. Although the dose thereof remarkably variesdepending upon the symptom, the age or the kind of the liver trouble, itis generally about 0.1 to 1,000 mg, preferably 2 to 500 mg, stillpreferably 5 to 100 mg, per adult and per day, which may be administeredat once or in several portions a day.

The preparation of a medicine containing the compound of the presentinvention is carried out by using conventional carries according to anordinary method.

More precisely, in the production of a solid preparation for oraladministration, a filler and, if necessary, a binder, disintegratingagent, lubricant, coloring agent or corrigent are added to a principalagent and the obtained mixture is converted into a tablet, coatedtablet, granule, powder or capsule according to an ordinary method.

Examples of the filler include lactose, corn starch, sucrose, glucose,sorbitol, crystalline cellulose and silicon dioxide, while those of thebinder include polyvinyl alcohol, polyvinyl ether, ethylcellulose,methylcellulose, gum arabic, tragacanth, gelatin, shellac,hydroxypropylcellulose, hydroxypropylmethylcellulose, calcium citrate,dextrin and pectin. Examples of the lubricant include magnesiumstearate, talc, polyethylene glycol, silica and hardened vegetable oils,while the coloring agent may be any one permitted as the additive todrugs. The corrigent include powdered cacao, mentha herb, aromaticpowder, mentha oil, borneol and powdered cinnamon bark. Of course, thesetablets and granules may be coated with sugar, gelatin or othermaterial.

In preparing an injection containing the compound of the presentinvention, a principal agent is, if necessary, mixed with a pH adjustingagent, buffer, stabilizer, solubilizing agent or the like and convertedinto a subcutaneous, intramuscular or intravenous injection according toan ordinary method.

The above mentioned pharmacological effect of the invention compounds issupported by the pharmacological experiments procedures and results ofwhich are described below according to the compound groups (I-a) to(I-f).

Compound Group (I-a) Experimental Example 1a Effect on liver injuryinduced by D-galactosamine in rats Experimental method:

300 mg/kg of D-galactosamine was administered to male Fischer (F₃₄₄)rats weighing around 180 g by subcutaneous injection to induce liverinjury. Each compound was dissolved in distilled water was given by oraladministration in a dose of 50 mg/kg one hour after the injection ofD-galactosamine.

The D-galactosamine was used in the form of a solution having aconcentration of 200 mg/ml, obtained by dissolving D-galactosamine in aphysiological saline solution to obtain a dilute D-galactosaminesolution and adjusting the pH of the dilute solution to 7.0 with 10Naqueous potassium hydroxide.

Blood was collected from the rat's tail vein 48 h after the injection ofD-galactosamine. The blood coagulation time was determined by thehepaplastin test (HPT) and GPT activity in the blood plasma wasdetermined by an enzymatic method.

The inhibition (%) of liver injury by each compound is shown in Table1a.

Experimental Example 2a Effect on liver injury induced by carbontetrachloride (CC14) Experimental method:

0.5 ml/kg of carbon tetrachloride was given to male Fischer (F₃₄₄) ratsweighing around 180 g by intraperitoneal injection to induce liverinjury. In this test, carbon tetrachloride was diluted to a finalconcentration of 0.25 ml/ml with olive oil.

Each compound dissolved in distilled water was given by oraladministration in a dose of 100 mg/kg one hour before the administrationof carbon tetrachloride.

Blood was collected from the rat's tail vein 24 h after the injection ofcarbon tetrachloride. GPT activity in plasma as an index of the liverinjury was determined by an enzymatie method. The inhibition (%) of theliver injury by each compound is shown in Table 2a.

Compound Group (I-b) Experimental Example 1b

The method was conducted in the same way as shown in ExperimentalExample 1a except that 400 mg/kg of D-galactosamine was used in itssolution in physiological saline and each test compound was administeredin a dose of 100 mg/kg in 0.5% methylcellulose solution. Results areshown in Table 1b.

Experimental Example 2b

The test was conducted in the same manner as shown in ExperimentalExample 1b except that the test compound was orally administered to therats in a dose of 100 mg/kg in 0.5% methylcellulose solution. Resultsare shown in Table 2b.

Compound Group (I-c) Experimental Examples 1c and 2c

The tests were conducted in the same ways as shown in ExperimentalExamples 1a and 2a, respectively. Results are shown in Tables 1c and 2c,respectively.

Compound Group (I-d) Experimental Example 1d

The test was conducted in the same manner as shown in ExperimentalExample 1a except that each test compound was used in its solution indistilled water or a suspension in 0.5% methylcellulose solution.Results are shown in Table 1d.

Experimental Example 2d

The test was conducted in the same way as shown in Experimental Example2a except that each test compound was used in a solution in distilledwater. Results are shown in Table 2d.

Compound Group (I-e) Experimental Example 1e

The test was conducted in the same way as shown in Experimental Example1a except that 400 mg/kg of D-galactosamine was administered and eachtest compound was used in a dose of 100 mg/kg in a suspension of 0.5%aqueous methylcellulose solution. Results are shown in Table 1e.

Experimental Example 2e

The test was conducted in the same way as shown in Experimental Example2a except that each test compound was used in a suspension of 0.5%aqueous methylcellulose solution. Results are shown in Table 2e.

Compound Group (I-f) Experimental Example 1f

The test was conducted in the same way as shown in Experimental Example1a except that 400 mg/kg of D-galactosamine was administered in itsphysiological saline solution and each test compound was used in anamount of 100 mg/kg in 0.5% methylcellulose liquid. Results are shown inTable 1f.

Experimental Example 2f

The test was conducted in the same way as shown in Experimental Example1a except that each test compound was used in an amount of 100 mg/kg ina suspension in 0.5% methylcellulose solution. Results are shown inTable 2f.

Toxicological Test of Compound Groups (I-a) to (I-f)

Male ddy mice being 7 weeks old and weighing around 30 g were used. 800mg/kg of the respective compounds shown in Tables 1a, 1b, 1c, 1d and 1fand the respective compounds 1, 3, 6 and 7 of Table 1e were administeredorally to the mice for 4 days. No mouse died.

                  TABLE 1a                                                        ______________________________________                                         ##STR42##                                                                    Compound                                                                      No.                        Inhibition                                         (Example                   ratio (%)                                          No.)     R.sup.1     R.sup.2 R.sup.3 HPT  GPT                                 ______________________________________                                        Compound 1                                                                             CH.sub.2 CH.sub.2 CH.sub.3                                                                H       H       88   90                                  (Example 2)                                                                   Compound 2                                                                             CH.sub.3    CH.sub.3                                                                              H       96   78                                  (Example 4)                                                                   Compound 3                                                                             CH.sub.3    H       CH.sub.3                                                                              94   81                                  (Example 6)                                                                   Compound 4                                                                             CH.sub.2 CH.sub.3                                                                         H       CH.sub.3                                                                              100  100                                 (Example 8)                                                                   Compound 5                                                                             CH.sub.2 CH.sub.3                                                                         H       CH.sub.2 CH.sub.3                                                                     96   82                                  (Example 11)                                                                  Compound 6                                                                             H           H       CH.sub.3                                                                              51   45                                  (Example 13)                                                                  Compound 7                                                                             H           (CH.sub.2).sub.2                                                                            86   56                                    (Example 15)                                                                  Compound 8                                                                             H           (CH.sub.2).sub.3                                                                            100  92                                    (Example 17)                                                                  ______________________________________                                    

                  TABLE 2a                                                        ______________________________________                                                      Inhibition ratio (%)                                            Compound No.  GPT                                                             ______________________________________                                        Compound 1    96                                                              Compound 2    88                                                              Compound 3    98                                                              Compound 4    80                                                              ______________________________________                                    

                                      TABLE 1b                                    __________________________________________________________________________     ##STR43##                                                                                                   Inhibition                                                                    ratio                                          Compound No.                   (%)                                            (Example No.)                                                                          X    R                HPT GPT                                        __________________________________________________________________________    Compound 1                                                                             S    H                96  91                                         (Example 1)                                                                   Compound 2                                                                             S    CH.sub.2 CH.sub.2 CH.sub.3                                                                     94  84                                         (Example 10)                                                                  Compound 3                                                                             S    CH.sub.2 CH.sub.2 OH                                                                           94  97                                         (Example 11)                                                                  Compound 4                                                                             S    (CH.sub.2).sub.3 OH                                                                            98  98                                         (Example 12)                                                                  Compound 5 (Example 13)                                                                S                                                                                   ##STR44##       65  43                                         Compound 6                                                                             S    CH.sub.2 CH.sub.2 OCH.sub.3                                                                    93  79                                         (Example 14)                                                                  Compound 7 (Example 15)                                                                S                                                                                   ##STR45##       96  92                                         Compound 8                                                                             S    CH.sub.2 COONa   97  97                                         (Example 3)                                                                   Compound 9                                                                              S   CH.sub.2 CH.sub.2 COONa                                                                        99  100                                        (Example 16)                                                                  Compound 10                                                                            S    (CH.sub.2).sub.3 COONa                                                                         99  89                                         (Example 17)                                                                  Compound 11                                                                            S    (CH.sub.2).sub.4 COONa                                                                         98  96                                         (Example 18)                                                                  Compound 12                                                                            S    (CH.sub.2).sub.5 COONa                                                                         75  69                                         (Example 19)                                                                  Compound 13 (Example 20)                                                               S                                                                                   ##STR46##       99  99                                         Compound 14 (Example 21)                                                               S                                                                                   ##STR47##       50  35                                         Compound 15 (Example 22)                                                               S                                                                                   ##STR48##       90  73                                         Compound 16                                                                            S    CH.sub.2 CONH.sub.2                                                                            94  86                                         (Example 23)                                                                  Compound 17 (Example 4)                                                                S                                                                                   ##STR49##       99  97                                         Compound 18 (Example 24)                                                               S                                                                                   ##STR50##       50  51                                         Compound 19  (Example 25)                                                              S                                                                                   ##STR51##       90  69                                         Compound 20 (Example 26)                                                               S                                                                                   ##STR52##       71  43                                         Compound 21 (Example 2)                                                                S                                                                                   ##STR53##        93*                                                                               93*                                       Compound 22 (Example 8)                                                                S                                                                                   ##STR54##       69  67                                         Compound 23 (Example 9)                                                                S                                                                                   ##STR55##       92  77                                         Compound 24 (Example 27)                                                               S                                                                                   ##STR56##       90  86                                         Compound 25                                                                            S    CH.sub.2 COOC.sub.2 H.sub.5                                                                    61  34                                         (Example 5)                                                                   Compound 26 (Example 6)                                                                 ##STR57##                                                                         CH.sub.3         100 100                                        Compound 27 (Example 28)                                                                ##STR58##                                                                         CH.sub.2 CH.sub.2 OH                                                                           65  54                                         Compound 28 (Example 7)                                                                 ##STR59##                                                                         CH.sub.3         98  95                                         Compound 29 (Example 29)                                                                ##STR60##                                                                         CH.sub.2 CH.sub.2 OH                                                                           84  63                                         Compound 30 (Example 30                                                                 ##STR61##                                                                         CH.sub.2 COOH    33  53                                         Compound 31 (Example 31)                                                                ##STR62##                                                                         CH.sub.2 CH.sub.2 COOH                                                                         37  26                                         Compound 32 (Example 32)                                                                ##STR63##                                                                         (CH.sub.2).sub.3 COOH                                                                          25  23                                         __________________________________________________________________________

                  TABLE 2b                                                        ______________________________________                                                      Inhibition ratio (%)                                            Compound No.  GPT                                                             ______________________________________                                        compound 3    47                                                              compound 4    93                                                              compound 8    53                                                              compound 9    98                                                              compound 10   43                                                              compound 11   90                                                              compound 13   86                                                              compound 16   61                                                              compound 17   98                                                              compound 21   34                                                              compound 25   21                                                              compound 26   97                                                              compound 28   97                                                              ______________________________________                                    

                  TABLE 1c                                                        ______________________________________                                         ##STR64##                                                                                              Inhibition                                          Compound No.              ratio (%)                                           (Example No.)                                                                           R.sup.1       R.sup.2                                                                              R.sup.3                                                                            HPT   GPT                                 ______________________________________                                        Compound 1                                                                              CH.sub.2 CH.sub.2 CH.sub.3                                                                  H      H    78    77                                  (Example 2)                                                                   Compound 2                                                                              CH.sub.2 CH.sub.3                                                                           H      H    75    78                                  (Example 4)                                                                   Compound 3                                                                              CH.sub.3      H      H    89    73                                  (Example 6)                                                                   Compound 4                                                                              CH.sub.2 OCH.sub.3                                                                          H      H    67    49                                  (Example 8)                                                                   Compound 5                                                                              CH.sub.2 OCH.sub.2 CH.sub.3                                                                 H      H    75    73                                  (Example 10)                                                                  Compound 6 (Example 12)                                                                  ##STR65##          67      60                                      Compound 7                                                                              CH.sub.2 CH.sub.2 O                                                                            H      51    12                                    (Example 14)                                                                  ______________________________________                                    

                  TABLE 2c                                                        ______________________________________                                                      Inhibition ratio (%)                                            Compound No.  GPT                                                             ______________________________________                                        Compound 3    77                                                              Compound 4    72                                                              Compound 6    94                                                              Compound 7    84                                                              ______________________________________                                    

                                      TABLE 1d                                    __________________________________________________________________________                                      Inhibition                                                                    ratio                                                                         (%)                                         Compound No.                                                                          Structural formula        HPT                                                                              GPT                                      __________________________________________________________________________    Compound 1                                                                             ##STR66##                100                                                                              89                                       Compound 2                                                                             ##STR67##                100                                                                              88                                       Compound 4                                                                             ##STR68##                91 84                                       Compound 5                                                                             ##STR69##                24 23                                       Compound 6                                                                             ##STR70##                76 64                                       Compound 7                                                                             ##STR71##                58 37                                       Compound 8                                                                             ##STR72##                61 28                                       Compound 10                                                                            ##STR73##                25 35                                       Compound 12                                                                            ##STR74##                85 85                                       Compound 14                                                                            ##STR75##                85 90                                       Compound 16                                                                            ##STR76##                41 25                                       Compound 18                                                                            ##STR77##                62 60                                       Compound 20                                                                            ##STR78##                93 87                                       Compound 22                                                                            ##STR79##                77 74                                       Compound 24                                                                            ##STR80##                59 40                                       Compound 26                                                                            ##STR81##                48 53                                       Compound 28                                                                            ##STR82##                45 44                                       Compound 29                                                                            ##STR83##                75 53                                       Compound 30                                                                            ##STR84##                22 46                                       Compound 31                                                                            ##STR85##                92 89                                       Compound 32                                                                            ##STR86##                88 80                                       Compound 33                                                                            ##STR87##                73 82                                       Compound 34                                                                            ##STR88##                17 37                                       Compound 35                                                                            ##STR89##                80 76                                       Compound 36                                                                            ##STR90##                68 59                                       Compound 37                                                                            ##STR91##                44 52                                       __________________________________________________________________________

                  TABLE 2d                                                        ______________________________________                                                      Inhibition ratio (%)                                            Compound No.  GPT                                                             ______________________________________                                        compound 1    90                                                              compound 2    99                                                              compound 16   73                                                              compound 18   82                                                              compound 26   55                                                              compound 28   75                                                              compound 33   99                                                              ______________________________________                                    

                                      TABLE 1e                                    __________________________________________________________________________                                         Inhibition                               Test                                 ratio                                    compound                             (%)                                      No.    Structural formula            HPT                                                                              GPT                                   __________________________________________________________________________    compound 1 (Ex. 1)                                                                    ##STR92##                    62 92                                    compound 2 (Ex. 2)                                                                    ##STR93##                    57 54                                    compound 3 (Ex. 3)                                                                    ##STR94##                    62 92                                    compound 4 (Ex. 4)                                                                    ##STR95##                    59 89                                    compound 5 (Ex. 5)                                                                    ##STR96##                    51 59                                    compound 6 (Ex. 6)                                                                    ##STR97##                    58 56                                    compound 7 (Ex. 7)                                                                    ##STR98##                    43 72                                    compound 8 (Ex. 8)                                                                    ##STR99##                    55 87                                     compound 9 (Ex. 9)                                                                   ##STR100##                   49 53                                    comound 10                                                                            ##STR101##                   43 72                                    compound 11 (Ex. 11)                                                                  ##STR102##                   68 76                                    compound 12 (Ex. 12)                                                                  ##STR103##                   45 63                                    __________________________________________________________________________

                  TABLE 2e                                                        ______________________________________                                                      Inhibition ratio (%)                                            Compound No.  GPT                                                             ______________________________________                                        compound 1    97                                                              compound 3    97                                                              compound 4    94                                                              compound 5    91                                                              compound 6    66                                                              compound 7    91                                                              compound 8    82                                                              compound 9    42                                                              compound 10   75                                                              ______________________________________                                    

                                      TABLE 1f                                    __________________________________________________________________________                                    Inhibition                                    Test                            ratio                                         compound                        (%)                                           No.    Structural formula       HPT GPT                                       __________________________________________________________________________            ##STR104##              100 84                                        2                                                                                     ##STR105##              83  76                                        3                                                                                     ##STR106##              100 100                                       4                                                                                     ##STR107##              100 89                                        5                                                                                     ##STR108##              67  97                                        6                                                                                     ##STR109##              100 100                                       7                                                                                     ##STR110##              67  83                                        8                                                                                     ##STR111##              96  100                                       9                                                                                     ##STR112##              67  88                                        10                                                                                    ##STR113##              96  100                                       11                                                                                    ##STR114##              68  97                                        12                                                                                    ##STR115##              76  75                                        13                                                                                    ##STR116##              17  50                                        14                                                                                    ##STR117##              32  33                                        15                                                                                    ##STR118##              50  42                                        16                                                                                    ##STR119##              76  96                                        17                                                                                    ##STR120##              70  91                                        __________________________________________________________________________

                                      TABLE 2f                                    __________________________________________________________________________                                    Inhibition                                    Test                            ratio                                         compound                        (%)                                           No.    Structural formula       HPT GPT                                       __________________________________________________________________________            ##STR121##              100 94                                        2                                                                                     ##STR122##              100 95                                        4                                                                                     ##STR123##              100 94                                        8                                                                                     ##STR124##               75 89                                        9                                                                                     ##STR125##              100 97                                        12                                                                                    ##STR126##              100 92                                        17                                                                                    ##STR127##               75 89                                        __________________________________________________________________________

A symbolic reference to ^(*) in Table 1b shows administration of 50mg/kg.

The compounds of the invention can be prepared by various processes.Typical examples of the processes are described below according to therespective compound groups.

Compound Group (I-a) Preparation process A [Preparation of compounds ofthe general formula (I) wherein X represents a group of the formula:--S--] ##STR128## wherein R¹, R², and R³ are as defined above and R⁴represents H or a lower alkyl group.

In this process, an alcohol of the general formula (II) is reacted witha thiol of the general formula (III) to obtain an intended compound(IV). This reaction is conducted by an ordinary method without using anysolvent or in an organic solvent inert to the reaction selected from thegroup consisting of aromatic hydrocarbons such as benzene, toluene andxylene, ethers such as ethyl ether, isopropyl ether, tetrahydro-furanand dioxane, halogenated hydrocarbons such as dichloro-methane,chloroform and carbon tetrachloride, esters such as ethyl acetate,ketones such as acetone and methyl ethyl ketone, as well asacetonitrile, dimethylformamide and acetic acid under cooling with ice,at room temperature or under heating for several hours. The reactionproceeds easily when an acid such as sulfuric, p-toluenesulfonic orD-10-camphorsulfonic acid is used as the catalyst.

Preparation process B [Preparation of compounds of the general formula(I) wherein X represents a group of the formula: --S--] ##STR129##wherein Hal represents a halogen atom and R¹, R², R³ and R⁴ are asdefined above

In this process, a halogen compound of the general formula (V) isreacted with a thiol of the general formula (III) to obtain an intendedcompound (IV).

This reaction is conducted by an ordinary method without using anysolvent or in an organic solvent inert to the reaction selected from thegroup consisting of aromatic hydrocarbons such as benzene, toluene andxylene, ethers such as tetrahydro-furan and dioxane, ketones such asacetone and methyl ethyl ketone, alcohols such as methanol and ethanol,halogenated hydrocarbons such as chloroform and carbon tetrachloride, aswell as acetonitrile, dimethylformamide and dimethyl sulfoxide undercooling with ice, at room temperature or under heating for severalhours. The reaction proceeds easily when an alkali metal carbonate orhydrogencarbonate such as sodium hydrogen-carbonate, potassium carbonateor sodium carbonate, an alkali hydroxide such as sodium hydroxide orpotassium hydroxide, an organic base such as triethylamine, pyridine ordiethylaniline, or sodium hydride is used as a dehydrohalogenatingagent.

Preparation process C [Preparation of compounds of the general formula(I) wherein X represents a group of the formula: --S--] ##STR130##wherein R¹ and R³ are as defined above, R⁴ represents a hydrogen atom ora lower alkyl group, and R⁵ and R⁶ each represents a hydrogen atom or analkyl, aryl, arylalkyl, heteroalkyl or heteroarylalkyl group.

In this process, a compound of the general formula (VI) is reacted witha thiol of the general formula (III) to obtain an intended compound(VII). This reaction is conducted by an ordinary method without usingany solvent or in an organic solvent selected from the group consistingof aromatic hydrocarbons such as benzene, toluene, and xylene, etherssuch as tetrahydrofuran and dioxane, halogenated hydrocarbons such asdichloromethane, chloroform and carbon tetrachloride, ketones such asacetone and methyl ethyl ketone, esters such as ethyl acetate, as wellas acetonitrile and dimethylformamide under cooling with ice, at roomtemperature or by heating under reflux. When the reaction proceeds onlyslowly, an acid such as sulfuric, p-toluenesulfonic orD-10-camphorsulfonic acid can be used as the catalyst.

The compound (VII) thus obtained is an intended one of the presentinvention represented by the above general formula (I) wherein Xrepresents --S-- and R² represents ##STR131##

Preparation process D [Preparation of compounds of the general formula(I) wherein X represents of a group of the formula: --S--] ##STR132##wherein Hal represents a halogen atom and R¹, R², R³ and R⁴ are asdefined above.

In this process, a thiol of the general formula (VIII) is reacted with ahalogen compound of the general formula (IX) under the same conditionsas those of the preparation process B to obtain an intended compound(IV). Preferred results are obtained when the base shown with referenceto the preparation process (B) is used.

The halogen atoms used in the preparation processes B and D includebromine, chlorine and iodine. Usually bromine or chlorine is used.

Preparation process E [Preparation of compounds of the general formula(I) wherein X represents a group of the formula: --S-- and R⁴ representsa hydrogen atom] ##STR133## wherein R¹, R² and R³ are as defined aboveand R^(4') is the same as R⁴ but excluding the hydrogen atom, namely,R^(4') represents a lower alkyl group.

An ester of the general formula (X) which is one of the intendedcompounds can be hydrolyzed by an ordinary method to obtain an intendedcarboxylic acid of the general formula (IV)'. In particular, thehydrolysis is conducted by an ordinary method in the presence of a baseor acid in a solvent suitably selected from the group consisting ofwater, methanol, ethanol, hydrous methanol, hydrous ethanol, hydroustetrahydrofuran, hydrous acetonitrile and hydrous acetone. The basesinclude alkali metal carbonates such as sodium and potassium carbonatesand alkali hydroxides such as sodium and potassium hydroxides. The acidsinclude, for example, hydrochloric and sulfuric acids.

Preparation process F [Preparation of compounds of the general formula(I) wherein X represents a group of the formula: ##STR134## wherein R¹,R², R³ and R⁴ are as defined above.

In this process, an intended compound (XI) is prepared by oxidizing, forexample, an intended compound (IV) prepared by the above-describedprocess. In particular, the compound (IV) is dissolved in a solventselected from the group consisting of aromatic hydrocarbons such asbenzene, toluene and xylene, halogenated hydrocarbons such asdichloromethane, chloroform and carbon tetrachloride, water, alcoholssuch as methanol and ethanol, ethyl acetate, acetone and acetic acid,and an equimolar amount of an oxidizing agent such as hydrogen peroxide,peracetic acid, m-chloroperbenzoic acid or sodium hypochlorite is addedthereto under cooling with dry ice/alcohol or ice/water to conduct thereaction in an ordinary manner and to produce an intended sulfoxidecompound (XI).

Preparation Process G

Preparation of compounds of the general formula (I) wherein X representsa group of the formula: ##STR135## wherein R¹, R², R³ and R⁴ are asdefined above.

In this process, an intended compound (XII) is prepared by oxidizing, anintended compound (IV) prepared by, for example, the above-describedprocess. More particularly, the compound (IV) is dissolved in a solventselected from the group consisting of aromatic hydrocarbons such asbenzene, toluene and xylene, halogenated hydrocarbons such asdichloromethane, chloroform and carbon tetrachloride, water, alcoholssuch as methanol and ethanol, ethyl acetate, acetone and acetic acid,and at least two equivalents of an oxidizing agent such as hydrogenperoxide, peracetic acid, m-chloroperbenzoic acid, sodium hypochloriteor sodium m-periodate is added thereto under cooling with ice or at roomtemperature to conduct the reaction and thereby to obtain an intendedsulfone compound (XII).

In another preparation process, a sulfoxide compound (XI) prepared by,for example, the preparation process F is dissolved in a solvent such aschloroform and then an oxidizing agent such as m-chloroperbenzoic acidis added thereto to conduct the reaction.

Pharmacologically acceptable salts of the intended compounds (I) whichare also intended in the present invention can be produced by, forexample, reacting a carboxylic acid compound of the general formula (I)wherein R⁴ represents a hydrogen atom with an alkali hydrogencarbonatesuch as NaHCO₃ or KHCO₃, an alkali carbonate such as Na₂ CO₃ or K₂ CO₃or an alkali hydroxide such as NaOH or KOH to obtain a pharmacologicallyacceptable salt such as sodium or potassium salt thereof.

COMPOUND GROUP (I-b) Preparation Process A

Preparation of compounds of the general formula (I) wherein X representsa group of the formula: --S-- ##STR136## wherein Hal represents ahalogen atom and R is as defined above.

In this process, 5-(2-halogenoethyl)-1,3-benzodioxole of the generalformula (II) is reacted with a thiol of the general formula (III) toobtain an intended compound (IV).

This reaction is conducted by an ordinary method without using anysolvent or in an organic solvent inert to the reaction selected from thegroup consisting of benzene, ethanol, xylene, tetrahydrofuran,chloroform, carbon tetrachloride, N,N-dimethylformamide, etc. undercooling with ice, at room temperature or under heating for severalhours. The reaction is facilitated by using an inorganic base such assodium hydrogencarbonate, potassium carbonate, sodium carbonate orsodium hydroxide or an organic base such as triethylamine, pyridine,pyrimidine or N,N-diethylaniline as the dehydrohalogenating agent.

Preparation Process B

Preparation of compounds of the general formula (I) wherein X representa group of the formula: --S-- ##STR137## wherein Hal represents ahalogen atom and R is as defined above.

In this process, 2-(1,3-benzodioxol-5-yl)ethanethiol (V) is reacted witha halogenating agent of the general formula (VI) under the sameconditions as those of the preparation process A to obtain an intendedcompound (IV). Also in this process, preferred results are obtained whenthe base as described above with reference to the preparation process Ais used. The halogen atoms used in the preparation processes A and Binclude bromine, chlorine and iodine. Usually bromine or chlorine isused.

Preparation Process C

Preparation of compounds of the general formula (I) wherein X representsa group of the formula: --S-- ##STR138## wherein R⁷ represents a loweralkyl group and R¹⁰ represents a lower alkyloxycarbonyl, N,N'-bis(loweralkyl)aminocarbonyl or carbamoyl group.

In this process, a thiol (V) is reacted with an unsaturated compound ofthe general formula (VII) by an ordinary method without using anysolvent or in a solvent selected from the group consisting of, forexample, benzene, dichloromethane, tetrahydrofuran,N,N-dimethylformamide and ethanol under cooling with ice, at roomtemperature or by heating under reflux to obtain an intended compound(VIII). When the reaction proceeds only slowly, a catalyst such aspiperidine, triethylamine, sodium methylate, Triton B, sulfur orsulfuric acid can be used as the catalyst.

The compound (VIII) thus obtained is an intended one of the presentinvention represented by the above general formula (I) wherein Xrepresents --S-- and R represents ##STR139##

Preparation Process D

Preparation of compounds of the general formula (I) wherein X representsa group of the formula: --S-- ##STR140## wherein R is as defined above.

In this process, 5-ethenyl-1,3-benzodioxole (IX) is reacted with a thiolof the general formula (III) by an ordinary method without using anysolvent or in a solvent such as tetrahydrofuran under cooling with ice,at room temperature or by heating under reflux to obtain an intendedcompound (IV). When the reaction proceeds only slowly, a peroxide suchas benzoyl peroxide, or azobisisobutyronitrile can be used as thecatalyst.

Preparation Process E

Preparation of compounds of the general formula (I) wherein X representsa group of the formula: ##STR141## wherein R is as defined above.

In this process, an intended compound (X) is prepared by oxidizing, forexample, an intended compound (IV) prepared by the above-describedprocess. Particularly, the compound (IV) is dissolved in an solventselected from the group consisting of aromatic hydrocarbons such asbenzene, toluene and xylene, halogenated hydrocarbons such asdichloromethane, chloroform and carbon tetrachloride, water, alcoholssuch as methanol and ethanol, ethyl acetate, acetone and acetic acid,and an equimolar amount of an oxidizing agent such as hydrogen peroxide,peracetic acid, m-chloroperbenzoic acid or sodium hypochlorite is addedthereto under cooling with dry ice/alcohol or ice/water to conduct thereaction in an ordinary manner and thereby to produce an intendedsulfoxide compound (X).

Preparation Process F

Preparation of compounds of the general formula (I) wherein X representsa group of the formula: ##STR142## wherein R is as defined above.

In this process, an intended compound (XI) is prepared by oxidizing anintended compound (IV) prepared by the above-described process. Moreparticularly, the compound (IV) is dissolved in a solvent selected fromthe group consisting of aromatic hydrocarbons such as benzene, tolueneand xylene, halogenated hydrocarbons such as dichloromethane, chloroformand carbon tetrachloride, water, alcohols such as methanol and ethanol,ethyl acetate, acetone and acetic acid, and two equivalents of anoxidizing agent such as hydrogen peroxide, peracetic acid,m-chloroperbenzoic acid, sodium hypochlorite or sodium m-periodate isadded thereto under cooling with ice or at room temperature to conductthe reaction and thereby to obtain an intended sulfone compound (XI).

In another preparation process, for example, a sulfoxide compound (X)prepared by the preparation process E is dissolved in a solvent such aschloroform and an oxidizing agent such as m-chloroperbenzoic acid isadded thereto to conduct the reaction.

Preparation Process G

Preparation of compounds of the general formula (I) wherein X representsa group of the formula: --S-- ##STR143## wherein n represents an integerof 1 to 5 and R¹¹ represents a lower alkyl, aryl, or heteroaryl group.

In this process, [2-(1,3-benzodioxol-5-yl)ethyl]thio derivative of thegeneral formula (XI) as it is or in the form of a solution in, forexample, benzene, dichloromethane, chloroform, tetrahydrofuran orN,N-dimethylformamide is mixed with a base such as pyridine,triethylamine, N,N-dimethylaniline or sodium carbonate as thedehydrohalogenating agent. An acid halide of the general formula: (XII)is added to the mixture to conduct the reaction and thereby to obtain anintended compound (XIII). Pyridine can be used as both the solvent andthe dehydrohalogenating agent. The reaction is conducted by cooling withwater or by heating under reflux.

Preparation Process H

Preparation of compounds of the general formula (I) wherein X representsa group of the formula: --S-- ##STR144## wherein N represents an integerof 1 to 5.

A [2-(1,3-benzodioxol-5-yl)ethyl]thio derivative (XIV) produced by, forexample, the above-described process A, B or D is dissolved in a solventsuch as benzene, chloroform or dimethylformamide. A chlorinating agentsuch as thionyl chloride, oxalyl chloride, phosphorus oxychloride orphosphorus pentachloride is added to the solution to conduct thereaction under cooling with ice, at room temperature or by heating underreflux to obtain an acid chloride derived from the compound (XIV). Asolution of glycine (XV) in, for example, an aqueous sodiumhydrogencarbonate solution, aqueous sodium carbonate solution or aqueoussodium hydroxide solution under stirring under cooling with ice/water toconduct the reaction and thereby to obtain an intended glycinamide(XVI).

The compound (XVI) prepared by this process is an intended compound ofthe general formula (I) wherein X represents --S-- and R² represents--(CH₂)_(n) --CONHCH₂ COOH.

Preparation Process I

Preparation of compounds of the general formula (I) wherein X representsa group of the formula: --S-- ##STR145## wherein Hal represents ahalogen atom.

A 5-(2-halogenoethyl)-1,3-benzodioxole of the general formula (II) andthiourea of the formula (XVII) are dissolved in a solvent such asmethanol or ethanol to conduct the reaction at room temperature or byheating under reflux to obtain a thiuronium salt (XVIII), which is thenhydrolyzed in the presence of a base such as sodium hydroxide orpotassium hydroxide in a suitably selected solvent such as water,methanol, ethanol, hydrous methanol or hydrous ethanol at roomtemperature or by heating under reflux to obtain intended2-(1,3-benzodioxol-5-yl)ethanethiol (V). The halogen atoms includebromine, chlorine and iodine. Usually bromine or chlorine is used.

Preparation Process J

Preparation of compounds of the general formula (I) wherein X representsa group of the formula: --S-- ##STR146## wherein n represents an integerof 1 to 5 and R³ and R⁴ may be the same or different from each other andeach represent a hydrogen atom or a lower alkyl group,

The carboxylic acid prepared by the preparation process A, B or D or itsreactive derivative is reacted with an amino compound of the generalformula (XIX) to form an amide which is an intended compound of theformula (XX).

The reactive derivatives of the compound (XIV) include acid halides suchas acid chlorides and acid bromides; acid azides; active esters thereofwith N-hydroxybenzotriazole and N-hydroxysuccinimides; symmetric acidanhydrides; and mixed acid ahydrides with alkylcarbonic acids andp-toluenesulfonic acid.

When a free carboxylic acid is used as the compound (XIV), the reactionis conducted preferably in the presence of a condensation agent such asdicyclohexylcarbodiimide or 1,1'-carbonyldiimidazole.

The reaction is conducted by using a compound (XIV) or its reactivederivative and a compound (XIX) in equimolar amounts or, alternatively,by using one of them in a small excess amount, in an organic solventinert to the reaction such as pyridine, tetrahydrofuran, dioxane, ether,benzene, toluene, xylene, methylene chloride, dichloroethane,chloroform, dimethylformamide, ethyl acetate or acetonitrile.

Depending on the kind of the reactive derivative, it is advantageous forconducting the reaction smoothly to add a base such as triethylamine,pyridine, picoline, lutidine, N-N-dimethylaniline, potassium carbonateor sodium hydroxide.

The reaction temperature is not particularly limited, since it variesdepending on the kind of the reactive derivative.

Pharmacologically acceptable salts of the intended compounds (I) whichare also intended products of the present invention can be prepared by,for example, reacting a carboxylic acid compound of the general formula(I) wherein R represents --(CH₂)_(n) --COOH, an amino acid compound ofthe general formula (I) wherein R represents ##STR147## or a glycinamidecompound (XVI) wherein R represents --(CH₂)_(n) --CONHCH₂ COOH with analkali hydrogencarbonate such as sodium hydrogencarbonate or potassiumhydrogencarbonate, an alkali carbonate such as sodium carbonate orpotassium carbonate or an alkali hydroxide such as sodium hydroxide orpotassium hydroxide to obtain a pharmacologically acceptable salt suchas the above-mentioned sodium or potassium salt.

COMPOUND GROUP (I-c) Preparation Process A

Preparation of compounds of the general formula (I) wherein R⁴represents a hydrogen atom ##STR148## wherein R¹, R² and R³ are asdefined above.

In this process, a dicarboxylic acid of the general formula (II) isheated to a temperature of 150° C. or higher in the absence of anysolvent to obtain an intended carboxylic acid (I)'.

Preparation Process B

Preparation of compounds of the general formula (I) wherein R²represents a hydrogen atom ##STR149## wherein R¹, R² and R³ are asdefined above.

In this process, an nitrile of the general formula (III) is hydrolyzedin an ordinary manner to obtain an intended carboxylic acid (I)'.

Particularly, the hydrolysis is conducted by an ordinary method in thepresence of a base in a solvent suitably selected from the groupconsisting of water, alcohols such as methanol, ethanol and ethyleneglycol, hydrous alcohols such as hydrous methanol, hydrous ethanol,hydrous ethylene glycol, hydrous diethylene glycol and hydrous ethyleneglycol, monoethyl ether, etc. The bases used herein include, forexample, potassium hydroxide, sodium hydroxide, and barium hydroxide.

Preparation Process C

When R¹ in the general formula (I) is a lower alkoxy-lower alkyl group,the intended compound can be prepared also by the following process:##STR150## wherein R², R³ and R⁴ are as defined above, X represents ahalogen atom, M represents an alkali metal atom, "Alkyl" represents alower alkyl group which is a straight-chain or branched one having 1 to6 carbon atoms as described above, and "Alkylene" represents an alkylenegroup derived from the above-mentioned alkyl group.

In this process, a halide of the general formula (IV) is reacted with analcoholate of the general formula (V) by an ordinary method in anorganic solvent selected from the group consisting of, for example,tetrahydrofuran, dimethylformamide, methanol, ethanol and 1-propanolunder cooling with ice, at room temperature or under heating to obtainan intended compound (VI). The halogen atoms usable in this processinclude, for example, bromine, chlorine and iodine atoms. The alkalimetal atoms include, for example, sodium and potassium.

The compound (VI) obtained by this process is an intended compound ofthe present invention which is represented by the general formula (I)wherein R¹ represents -Alkylene-O-Alkyl.

Preparation Process D

An intended compound of the general formula (I) wherein R¹ represents alower alkoxy-lower alkyl group of the formula: --CH₂ --O-Alkyl in which"Alkyl" represents a lower alkyl group having 1 to 6 carbon atoms can beproduced also by the following process: ##STR151## wherein R², R³, R⁴and "Alkyl" are as defined above.

In this process, an acetoxymethyl compound of the general formula (VII)is reacted with a compound of the general formula (VIII) in the presenceof an acid catalyst at room temperature or under heating to obtain anintended compound of the general formula (IX). This reaction ispreferably conducted in the presence of a lower alcohol such asmethanol, ethanol, 1-propanol or 2-propanol.

The acid catalysts include, for example, hydrochloric, sulfuric,p-toluenesulfonic and D-10-camphorsulfonic acids.

The compound (IX) prepared by this process is an intended compound ofthe present invention which is represented by the general formula (I)wherein R¹ represents --CH₂ --O-Alkyl.

Preparation Process E

A compound of the general formula (I) wherein R¹ and R³ form together aring can be prepared also by the following process: ##STR152## whereinR², R³ and R⁴ are as defined above and n represents an integer of 1 to3.

An acrylic acid derivative of the general formula (X) is subjected to anintramolecular cyclization to obtain an intended compound (XI) of thepresent invention. This reaction is conducted by an ordinary methodwithout using any solvent or in an organic solvent such as benzene,ethanol, tetrahydrofuran or dimethylformamide under cooling with ice, atroom temperature or under heating for several hours. The reactionproceeds easily in the presence of a base such as sodium ethylate,potassium t-butoxide or sodium hydride.

The compound (XI) obtained by the above-mentioned process is one of theintended compounds of the present invention.

COMPOUND GROUP (I-d) Preparation Process A

Preparation of compounds of the general formula (I) wherein X representsa group of the formula: --S-- ##STR153## wherein Y represents a halogenatom or a methanesulfonyloxy or p-toluenesulfonyloxy group and A, R¹,R², R³, R⁴ and R⁵ are as defined above.

In this process, a thiol of the general formula (II) is reacted with acompound of the general formula (III) to form an intended compound (IV).This reaction is conducted by an ordinary method without using anysolvent or in an organic solvent inert to the reaction selected from thegroup consisting of aromatic hydrocarbons such as benzene, toluene andxylene, ethers such as tetrahydrofuran and dioxane, ketones such asacetone and methyl ethyl ketone, alcohols such as methanol and ethanol,halogenated hydrocarbons such as chloroform and carbon tetrachloride,acetonitrile, N,N-dimethylformamide and dimethyl sulfoxide under coolingwith ice, at room temperature or under heating for several hours. Thereaction proceeds easily when an alkali metal carbonate orhydrogencarbonate such as sodium hydrogencarbonate, potassium carbonateor sodium carbonate, an alkali hydroxide such as sodium hydroxide orpotassium hydroxide, or an organic base such as triethylamine, pyridineor diethylaniline is used as the dehydrohalogenating agent, or an agentfor removing methanesulfonic or p-toluenesulfonic acid.

Preparation Process B

Preparation of compounds of the general formula (I) wherein X representsa group of the formula --S-- ##STR154## wherein Y represents a halogenatom or a methanesulfonyloxy or p-toluenesulfonyloxy group and A, R¹,R², R³, R⁴ and R⁵ are as defined above.

In this process, a compound of the general formula (V) is reacted with athiol of the general formula (VI) under the same conditions as those ofpreparation process A to obtain an intended compound (IV). Also in thisprocess, preferred results are obtained when a base described above withreference to the preparation process A is used.

The halogen atoms used in the preparation processes A and B includechlorine, bromine and iodine. Usually bromine or chlorine is used.

Preparation Process C

Preparation of compounds of the general formula (I) wherein X representsa group of the formula: --S-- ##STR155## wherein A, R¹, R², R³, R⁴ andR⁵ are as defined above.

A compound of the general formula (VII) is reacted with a thiol of thegeneral formula (VI) to obtain an intended compound (IV). This reactionis conducted by an ordinary method without using any solvent or in asolvent selected from the group consisting of aromatic hydrocarbons suchas benzene, toluene and xylene, ethers such as tetrahydrofuran anddioxane, halogenated hydrocarbons such as dichloromethane, chloroformand carbon tetrachloride, ketones such as acetone and methyl ethylketone, esters such as ethyl acetate, acetonitrile andN,N-dimethylformamide under cooling with ice, at room temperature or byheating under reflux.

When the reaction proceeds only slowly, a peroxide such as benzoylperoxide or a catalyst such as azobisisobutyronitrile can be added.

Preparation Process D

Preparation of compounds of the general formula (I) wherein X representsa group of the formula: --S-- ##STR156## wherein R¹, R², R³, R⁴ and R⁵are as defined above.

A cyano compound of the general formula (VIII) which is also an intendedcompound is reacted with carbon dioxide in the presence of a base toobtain an intended carboxylic acid of the general formula (IX). In thisprocess, a compound (VIII) as it is or in the form of a solution in ananhydrous ether solvent such as anhydrous ethyl ether, anhydroustetrahydrofuran or anhydrous ethylene glycol dimethyl ether is reactedwith a strong base such as n-butyllithium, phenyllithium, lithiumdiisopropylamide or sodium amide under cooling with dry ice/alcohol orwith ice, and the reaction product is further reacted with carbondioxide under cooling with dry ice/alcohol or with ice to obtain thecompound (IX).

The compound (IX) is an intended one of the present inventionrepresented by the general formula (I) wherein X presents --S-- and Arepresents ##STR157##

Preparation Process E

Preparation of Compounds of the general formula (I) wherein X representsa group of the formula: --S-- ##STR158## wherein R¹, R², R³, R⁴, R⁵, R⁹,R¹⁰ and p are as defined above.

A sodium sulfonate of the general formula (X) is suspended in, forexample, benzene or chloroform. Then, thionyl chloride or the like isadded thereto and the reaction is conducted by heating under reflux toobtain an acid chloride of the compound (X). This product is reactedwith an amine (XI) in the presence of a base in the absence of anysolvent or in a solvent such as water, methanol, ethanol, benzene,dichloromethane, tetrahydrofuran or N,N-dimethylformamide to obtain anintended compound (XII). The bases usable herein include, for example,the amine (XI) per se, pyridine, N,N-dimethylaniline or triethylamine.

The compound (XII) is an intended one of the present inventionrepresented by the general formula (I) wherein X represents --S-- and Arepresents ##STR159##

Preparation Process F

Preparation of compounds of the general formula (I) wherein X representsa group of the formula ##STR160## wherein A, R¹, R², R³, R⁴ and R⁵ areas defined above.

A compound (IV) which also is an intended compound prepared by, forexample, the above-described process is oxidized to obtain an intendedcompound (XIII). In this process, the compound (IV) is dissolved in asolvent selected from the group consisting of aromatic hydrocarbons suchas benzene, toluene and xylene, halogenated hydrocarbons such asdichloromethane, chloroform and carbon tetrachloride, water, alcoholssuch as methanol and ethanol, ethyl acetate, acetone and acetic acid andthen reacted with an equimolar amount of an oxidizing agent such ashydrogen peroxide, peracetic acid, m-chloroperbenzoic acid or sodiumhypochlorite by an ordinary method under cooling with dry ice/alcohol orwith ice/water to obtain the intended sulfoxide compound (XIII).

Preparation Process G

Preparation of compounds of the general formula (I) wherein X representsa group of the formula ##STR161## wherein A, R¹, R², R³, R⁴ and R⁵ areas defined above.

In this process, an intended compound (IV) obtained by, for example, theabove-described process is oxidized to obtain an intended compound(XIV). More particularly, the compound (IV) is dissolved in a solventselected from the group consisting of aromatic hydrocarbons such asbenzene, toluene and xylene, halogenated hydrocarbons such asdichloromethane, chloroform and carbon tetrachloride, water, alcoholssuch as methanol and ethanol, ethyl acetate, acetone and acetic acid. Atleast two equivalents of an oxidizing agent such as hydrogen peroxide,peracetic acid, m-chloroperbenzoic acid, sodium hypochlorite or sodiumm-periodate is added thereto under cooling with ice or at roomtemperature to conduct the reaction and thereby to obtain an intendedsulfone compound (XIV).

In another process, a sulfoxide compound (XIII) obtained by, forexample, the preparation process F is dissolved in a solvent such aschloroform and then an oxidizing agent such as m-chloroperbenzoic acidis added to the solution to conduct the reaction.

Pharmacologically acceptable salts of the intended compounds (I) whichare also intended products of the present invention can be prepared by,for example, reacting a compound of the general formula (I) wherein Arepresents ##STR162## represents --(CH₂)_(n) COOH or A represents##STR163## with sodium hydrogencarbonate, potassium hydrogencarbonate,sodium carbonate, potassium carbonate, sodium hydroxide or potassiumhydroxide to obtain a pharmacologically acceptable salt such as sodiumor potassium salt thereof.

COMPOUND GROUP (I-e) Preparation Process A ##STR164## wherein X, R¹ andY are as defined above.

That is, a thiol represented by the general formula (II) is reacted witha thio represented by the general formula (III) to obtain a compound (I)which is one of the objective compounds according to the presentinvention.

More precisely, the reaction of a compound (II) with a compound (III) iscarried out in the absence of any solvent or in the presence of asolvent inert to the reaction selected from among alcohols such asmethanol, ethanol and propanol, acetic acid and an aqueous solution ofpotassium iodide or the like either under cooling with ice or heating orat a room temperature by using an oxidizing agent such as iodine,hydrogen peroxide, lead dioxide, oxygen, copper sulfate, ferricchloride, potassium permanganate, potassium ferricyanide, sulfurylchloride, dimethyl sulfoxide, sulfur dioxide or phosphorus pentachlorideaccording to an ordinary method to obtain a compound (I) which is one ofthe objective compounds.

Preparation Process B ##STR165## wherein X is as defined above; R²represents a lower alkyl, aryl or heteroaryl group and Hal represents ahalogen atom.

More precisely, the reaction of an alcohol represented by the generalformula (IV) with an acid halide represented by the general formula (V)is carried out in the absence of any solvent or in the presence of asolvent such as dichloromethane, chloroform, tetrahydrofuran orN,N-dimethylformamide by using a base such as pyridine, triethylamine,N,N-dimethylaniline, sodium carbonate or sodium hydrogencarbonate as adehydrohalogenating agent to obtain a compound (VI) which is one of theobjective compounds. In the reaction, pyridine can serve as both asolvent and a dehydrohalogenating agent. The reaction may be carried outeither under cooling with water or under reflux by heating.

The preparation of pharmacologically acceptable salts of the compounds(I), which are also among the objective compounds according to thepresent invention, can be carried out by, for example, reacting acompound represented by the general formula (I) wherein Y is ##STR166##with hydrochloric, sulfuric or hydrobromic acid, Thus, thehydrochloride, sulfate or hydrobromide of the compound (I) is obtained.

COMPOUND GROUP (I-f) Preparation Process A ##STR167## wherein theformulas (II) to (IV), R¹, R² and R³ are as defined above.

That is, an alcohol represented by the general formula (II) is reactedwith a mercaptoacetic acid represented by the general formula (III) toobtain a compound represented by the general formula (IV) which is oneof the objective compounds according to the present invention. Thisreaction is carried out in the absence of any solvent or in the presenceof an organic solvent inert to the reaction selected from among aromatichydrocarbons such as benzene, toluene and xylene; ethers such as ether,isopropyl ether, tetrahydrofuran and dioxane; halogenated hydrocarbonssuch as dichloromethane, chloroform and carbon tetrachloride; esterssuch as ethyl acetate; ketones such as acetone and methyl ethyl ketone;acetonitrile; dimethylformamide and acetic acid either under coolingwith ice or heating or at a room temperature for several hours accordingto an ordinary process. The progress of the reaction is facilitated byusing an acid such as sulfonic, p-toluenesulfonic orD-10-camphorsulfonic acid as a catalyst.

Preparation Process B ##STR168## wherein the formulas (V) and (VI), Halrepresents a halogen atom or a methanesulfonyloxy orp-toluenesulfonyloxy group and R¹, R², R³ and a are as defined above.

That is, a compound represented by the general formula (V) is reactedwith a mercaptoacetic acid represented by the formula (III) to obtain acompound represented by the general formula (VI) which is one of theobjective compounds according to the present invention.

More precisely, the above reaction is carried out in the absence of anysolvent or in the presence of an organic solvent inert to the reactionselected from among aromatic hydrocarbons such as benzene, toluene andxylene; ethers such as tetrahydrofuran and dioxane; ketones such asacetone and methyl ethyl ketone; alcohols such as methanol and ethanol;halogenated hydrocarbons such as chloroform and carbon tetrachloride;acetonitrile, N,N-dimethylformamide and dimentyl sulfoxide either undercooling with ice or heating or at a room temperature for several hoursaccording to an ordinary process. The progress of the reaction can befacilitated by using an alkali metal carbonate or hydrogencarbonate suchas sodium hydrogencarbonate or potassium or sodium carbonate; an alkalihydroxide such as sodium or potassium hydroxide; an organic base such astriethylamine, pyridine or diethylamine or sodium hydride as adehydrohalogenating, demethanesulfonating or de-p-toluenesulfonatingagent.

In the preparation processes A and B, the halogen atom includeschlorine, bromine, and iodine, among which bromine and iodine aregenerally used.

Preparation Process C ##STR169## wherein R⁴ and R⁵ may be the same ordifferent from each other and each represents a hydrogen atom or a loweralkyl group and R¹, R², R³ and n are as defined above.

That is, a carboxylic acid represented by the general formula (VI) or areactive derivative thereof, which can be prepared by, for example, theabove preparation process A or B, is reacted with an amine representedby the general formula (VII) to obtain a compound represented by thegeneral formula (VIII) which is one of the objective compounds accordingto the present invention.

The reactive derivative of the compound (VI) includes acid halides suchas acid chloride and acid bromide; acid azide; reactive esters thereofwith N-hydroxybenzotriazole, N-hydroxysuccinimide or the like; symmetricacid anhydride and mixed acid anhydride thereof with alkylcarbonic acidand p-toluenesulfonic acid.

When a compound (VI) having a free carboxyl group is used, it ispreferred to carry out the reaction in the presence of a condensationagent such as dicyclohexylcarbodiimide or 1,1'-carbonyldiimidazole.

The reaction is carried out by using a compound (VI) or a reactivederivative thereof and a compound (VII) in equimolar amounts or in suchamounts that either of then is in slight excess over the other in anorganic solvent inert to the reaction selected from among pyridine,tetrahydrofuran, dioxane, ether, benzene, toluene, xylene, methylenechloride, dichloroethane, chloroform, dimethylformamide, ethyl acetate,acetonitrile and the like.

When some kinds of the reactive derivatives are used, the addition of abase such as triethylamine, pyridine, picoline, lutidine,N,N-dimethylaniline, potassium carbonate or sodium hydroxideadvantageously serves to make the reaction proceed smoothly.

The reaction temperature is not particularly limited and variesdepending upon the kind of the reactive derivative used.

Preparation Process D ##STR170## wherein R¹, R², R³ and n are as definedabove.

More precisely, a compound (VI), which can be prepared by thepreparation process A or B, is dissolved in a solvent such as benzene,chloroform or dimethylfromamide, followed by the addition of thionylchloride, oxalyl chloride, phosphorus oxychloride or phosphoruspentachloride. The obtained mixture was reacted either under coolingwith ice or reflux by heating or at a room temperature to prepare anacid chloride of the compound (VI). A solution of glycine (IX) in anaqueous solution of sodium hydrogencarbonate, sodium carbonate or sodiumhydroxide or the like is poured into the obtained reaction mixture understirring and cooling with ice to carry out the reaction. Thus, aglycinamide (X) which is one of the objective compounds is obtained.

The glycinamide (X) obtained above corresponds to a compound representedby the general formula (I) wherein R⁴ or R⁵ is a carboxymethyl group andis thus one of the objective compounds according to the presentinvention.

The preparation of a pharmacologically acceptable salt of a compound(I), which is also one of the objective compounds according to thepresent invention, can be carried out by, for example, reacting acarboxylic acid (VI) corresponding to a compound represented by thegeneral formula (I) wherein Y is --CO₂ H or a glycinamide (X)corresponding to a compound represented by the general formula (I)wherein R⁴ or R⁵ is a carboxymethyl group with an alkalihydrogencarbonate such as sodium or potassium hydrogencarbonate, analkali carbonate such as sodium or potassium carbonate or an alkalihydroxide such as sodium or potassium hydroxide.

EXAMPLES OF THE INVENTION

The invention will be below illustrated in view of examples togetherwith preparation of starting materials for the invention compounds,according to the compounds groups (I-a) through (I-f).

COMPOUND GROUP (I-a) Preparative Example 12-(1,3-Benzodioxol-5-yl)-2-propanol ##STR171##

About 600 ml of 1.5M methyllithium (solution in ether) was added to 500ml of tetrahydrofuran. A suspension of 93.45 g of5-acetyl-1,3-benzodioxole in 900 ml of tetrahydrofuran was added theretounder cooling at -20° C. The mixture was stirred under these conditionsfor 1 h. Water was added to the reaction mixture. The product wasextracted with ethyl acetate, washed with a saturated aqueous commonsalt solution and dried over anhydrous magnesium sulfate. Afterfiltration, the filtrate was concentrated to obtain 97 g of the intendedcompound in the form of an oil.

¹ H-NMR (90 MHz, CDCl₃) δ; 1.54 (s, 6H), 1.72 (bs, 1H), 5.88 (s, 2H),6.6-7.0 (m, 3H).

Preparative Example 2 2-(1,3-Benzodioxol-5-yl) Propene ##STR172##

14.52 g of 2-(1,3-benzodioxol-5-yl)-2-propanol was dissolved in 200 mlof benzene. A catalytic amount of p-toluenesulfonic acid monohydrate wasadded to the solution and the mixture was heated under reflux in ashort-neck Kjeldahl flask provided with a Dean-Stark reflux condenserfor 2.5 h. The reaction mixture was washed with a saturated aqueoussodium hydrogencarbonate solution and then with a saturated aqueouscommon salt solution and dried over anhydrous magnesium sulfate. Afterfiltration, the filtrate was concentrated to obtain 14.33 g of theintended compound in the form of an oil.

¹ H-NMR (90 MHz, CDCl₃) δ; 2.08 (bs, 3H), 4.8-5.0 (m, 1H), 5.19 (bs,1H), 5.89 (s, 2H), 6.5-7.0 m, 3H).

Preparative Example 3 1-(6-Methyl-1,3-benzodioxol-5-yl)ethanol##STR173##

32 ml of a 1.4M solution of methyllithium in diethyl ether was dissolvedin 50 ml of anhydrous tetrahydrofuran and the solution was cooled at-40° C. in a nitrogen atmosphere. 5.0 g of solid(6-methyl-1,3-benzodioxol-5-yl) carboxaldehyde was added to the solutionand the temperature was elevated to room temperature gradually over 1 h.Water was added to the reaction mixture. After extraction with either,the organic layer was washed with an aqueous common salt solution. Afterdrying over magnesium sulfate, the solvent was distilled off to obtain awhite solid, which was recrystallized from diisopropyl ether/n-hexane toobtain 2.8 g of the intended compound in the form of white crystals.

mp.; 61°-62° C.,; ¹ H-NMR (90 MHz, CDCl₃) δ; 1.39 (d, J=7 Hz, 3H), 1.72(bs, 1H), 2.22 (s, 3H), 4.99 (m, 1H), 5.83 (s, 2H), 6.53 (s, 1H), 6.94(s, 1H).

Preparative Example 4 1-(6-Methyl-1,3-benzodioxol-5-yl)-1-propanol##STR174##

A solution of 2.0 g of (6-methyl-1,3-benzodioxol-5-yl)carboxaldehyde in15 ml of anhydrous tetrahydrofuran was added dropwise at roomtemperature to a Grignard reagent prepared from 0.32 g of magnesiumribbon, 20 ml of anhydrous tetrahydrofuran and 1.4 g of bromoethane. Themixture was stirred for 2 h. A saturated ammonium chloride solution wasadded to the reaction mixture. The solvent was distilled off. Afterextraction with ethyl acetate followed by drying over magnesium sulfateand concentration under reduced pressure, the residue was purifiedaccording to silica gel column chromatography (ethyl acetate/hexane=2:8)to obtain 2.27 g of the intended compound in the form of white crystals.

mp.; 71°-72° C.; ¹ H-NMR (90 MHz, CDCl₃) δ; 0.92 (t, J=7 Hz, 3H),1.63-1.92 (m, 2H), 1.80 (bs, 1H), 2.20 (s, 3H), 4.72 (t, J=7 Hz, 1H),5.82 (s, 2H), 6.52 (s, 1H), 6.88 (s, 1H).

Preparative Example 5 1-(6-Ethyl-1,3-benzodioxol-5-yl)-1-propanol##STR175##

A solution of 3.2 g of (6-ethyl-1,3-benzodioxol-5-yl)carboxaldehyde in10 ml of anhydrous tetrahydrofuran was added dropwise at roomtemperature to a Grignard reagent prepared from 0.54 g of magnesiumribbon, 10 ml of anhydrous tetrahydrofuran and 2.4 g of bromoethane. Thereaction was conducted at that temperature for 2 h. A saturated aqueousammonium chloride solution was added to the reaction mixture. Thesolvent was distilled off. After extraction with ethyl acetate followedby drying over magnesium sulfate and concentration under reducedpressure, 3.9 g of the crude alcohol was obtained in the form of ayellow oil, which was used in the subsequent reaction withoutpurification.

¹ H-NMR (90 MHz, CDCl₃) δ; 0.96 (t, J=7 Hz, 3H), 1.18 (t, J=7 Hz, 3H),1.72 (m, 3H), 2.32-2.80 (m, 2H), 4.76 (t, J=7 Hz, 1H), 5.84 (s, 2H),6.58 (s, 1H), 6.88 (s, 1H).

Preparative Example 6 5,6-Methylenedioxyindan-1-ol ##STR176##

A solution of 30 g of 5,6-methylenedioxyindan-1-one in 120 ml oftetrahydrofuran was added dropwise to a suspension of 2.4 g of lithiumaluminum hydride in 160 ml of anhydrous tetrahydrofuran under coolingwith ice. The mixture was stirred at room temperature overnight. 2.4 mlof water, then 2.4 ml of 15% aqueous sodium hydroxide solution andfinally 7.2 ml of water were added thereto and insoluble substances werefiltered off. The filtrate was distilled and the residue was washed withdiisopropyl ether to obtain 24.3 g of the intended compound in the formof faint brown crystals.

mp.; 92°-94° C.; ¹ H-NMR (90 MHz, CDCl₃) δ; 1.76 (d, J=7 Hz, 1H), 1.93(m, 1H), 2.28-3.08 (m, 3H), 5.10 (m, 1H, 5.92 (s, 2H), 6.65 (s, 1H, 6.83(s, 1H).

Example 1 [{1-(1,3-Benzodioxol-5-yl)butyl}thio]acetic Acid ##STR177##

A mixture of 103 g of 1-(1,3-benzodioxol-5-yl)-1-butanol, 73.3 g ofmercaptoacetic acid, 0.1 g of D-10-camphorsulfonic acid and 500 ml ofbenzene was heated under reflux for 2 h. 2,000 ml of ether was added tothe reaction mixture. After washing with water, the product wasredissolved in 750 ml of 1N NaOH and then in 100 ml thereof. Thesolution thus obtained was washed with ether and then with chloroform,acidified with concentrated hydrochloric acid and extracted with 800 mland then 400 ml of ethyl acetate. The extract was washed with water,dried over magnesium sulfate and concentrated under reduced pressure toobtain 132 g of the crude product. It was purified according to silicagel column chromatography (ethyl acetate/hexane/formic acid=100:900:1)to obtain 127 g of the intended compound in the form of a colorless oil.This oil was crystallized from n-hexane to obtain 115 g of the titledcompound as a white crystalline powder. It was found to have a meltingpoint of 59° to 61° C.

¹ H-NMR (90 MHz, CDCl₃) δ; 0.88 (m, 3H, 1.12-1.52 (m, 2H, 1.78-1.94 (m,2H), 2.92 and 3.03 (ABq, J=15 Hz, 2H, 3.92 (t, J=7 Hz, 1H, 5.92 (s, 2H,6.68-6.80 (m, 3H).

Example 2 Sodium[{1-(1,3-benzodioxol-5-6l)butyl}thio]acetate ##STR178##

100 g of [{1-(1,3-benzodioxol-5-yl)butyl}thio]acetic acid was dissolvedin 500 ml of ethanol. 372 ml of 1N-aqueous sodium hydroxide solution wasadded thereto. Ethanol and water were removed from the reaction mixtureby azeotropic distillation and then ether was added to the residue tosolidify it. A precipitate thus formed was recovered by filtration anddried to obtain 102 g of the intended compound in the form of a whitepowder.

mp.; 193°-207° C. (dec.); ¹ H-NMR (400 MHz, DMSO-d₆) δ; 0.82 (t, J=7.3Hz, 3H), 1.11-1.26 (m, 2H), 1.59-1.77 (m, 2H), 2.64 and 2.73 (ABq,J=13.9 Hz, 2H), 3.87 (dd, J=9.2 Hz, 6.2 Hz, 1H), 5.97 (s, 2H), 6.71 (dd,J=8.1 Hz, 1.8 Hz, 1H), 6.79 (d, J=8.1 Hz, 1H), 6.84 (d, J=1.8 Hz, 1H),MS(FAB) m/z; 291 (MH⁻).

Example 3 [{2-(1,3-Benzodioxol-5-yl)-2-propyl}thio]acetic Acid##STR179##

600 ml of benzene, 59.5 g of mercaptoacetic acid and a catalytic amountof D-10-camphorsulfonic acid were added to 97 g of2-(1,3-benzodioxol-5-yl)-2-propanol and the mixture was heated underreflux for 4 h. The solvent was distilled off and the pH of the residuewas adjusted to 10 with 1N aqueous sodium hydroxide solution. Afterwashing with ethyl acetate, 4N hydrochloric acid was added thereto undercooling with ice to acidity the aqueous layer. After extraction withchloroform, the extract was washed with water and dried over anhydrousmagnesium sulfate. It was filtered and the filtrate was concentrated.The crystals thus formed were recrystallized form diisopropyl ether toobtain 62.70 g of the intended compound in the form of colorlesscrystals.

37.32 g of the intended compound was obtained also from 38.73 g of2-(1,3-benzodioxol-5-yl)propene in the same manner as that describedabove.

mp.; 78.5°-80° C.; ¹ H-NMR (90 MHz, CDCl₃) δ; 1.68 (s, 6H), 2.99 (s,2H), 5.88 (s, 2H), 6.64 (d, J=8.3 Hz, 1), 6.86 (dd, J=8.3 Hz, 2.5 Hz,1H), 6.99 (d, J=2.5 Hz, 1H), 8.0-9.0 (br, 1H).

Example 4 Sodium [{2-(1,3-benzodioxol-5-yl)-2-propyl}thio]acetate##STR180##

107.62 g of the intended compound in the form of colorless crystals wasobtained from 99.88 g of [{2-(1,3-benzodioxol-5-yl)-2-propyl}thio]aceticacid in the same manner as that of Example 2.

mp.; 229.5°-230.5° C.; ¹ H-NMR (400 MHz, DMSO-d₆) δ; 1.54 (s, 6H, 2.69(s, 2H), 5.98 (s, 2H), 6.80 (d, J=1.8 Hz, 1H), 6.88 (dd, J=8.1 Hz, 1.8Hz, 1H, 7.06 (d, J=1.8 Hz, 1H); MS(FAB)b m/z; 277 (MH⁻).

Example 5 [{1-(6-Methyl-1,3-benzodioxol-5-yl)ethyl}thio]acetic Acid##STR181##

3.7 g of mercaptoacetic acid and a catalytic amount ofD-10-camphorsulfonic acid were added to 3.2 g of1-(6-methyl-1,3-benzodioxol-5-yl)ethanol and the mixture was heatedunder reflux in 100 ml of benzene for 1 h. The reaction mixture waswashed with water and then extracted with a 1 1N sodium hydroxidesolution. The aqueous layer was washed with ethyl acetate, acidifiedwith 1N hydrochloric acid and extracted with chloroform. The organiclayer was dried over magnesium sulfate and the solvent was distilled offto obtain a crystalline residue. After recrystallization fromdiisopropyl ether, 4.2 g of the intended compound was obtained in theform of white crystals.

mp.; 93.5°-94.5° C.; ¹ H-NMR (90 MHz, CDCl₃) δ; 1.51 (d, J=7 Hz, 3H),2.26 (s, 3H), 2.92 and 3.12 (ABq, J≦16 Hz, 2H), 4.39 (q, J=7 Hz, 1H),5.85 (s, 2H), 6.564 (s, 1H), 6.94 (s, 1H), 10.12 (m, 1H).

Example 6 Sodium [{1-(6-Methyl-1,3-benzodioxol-5-yl)ethyl}thio]acetate##STR182##

4.0 g of the intended compound in the form of white crystals wasobtained from 3.85 g of[{1-(6-methyl-1,3-benzodioxol-5-yl)ethyl}thio]acetic acid in the samemanner as that of Example 2.

mp.; 189°-192° C. (dec.); ¹ H-NMR (400 MHz, DMSO-d₆) δ; 1.39 (d, J=7.0Hz, 3H), 2.24 (s, 3H), 2.78 (s, 2H), 4.28 (q, J=7.0 Hz, 1H), 5.92 (m,2H), 6.68 (s, 1H), 6.92 (s, 1H); MS(FAB) m/z; 277 (MH⁻).

EXAMPLE 7 [{1-(6-Methyl-1,3-benzodioxol-5-yl)-1-propyl}thio]acetic Acid##STR183##

2.27 g of 1-(6-methyl-1,3-benzodioxol-5-yl)-1-propanol, 0.1 g ofp-toluenesulfonic acid and 1.52 g of mercaptoacetic acid were dissolvedin 80 ml of benzene. The solution was heated under reflux for 12 h whilewater was removed. The reaction mixture was poured into water. Theaqueous layer was made alkaline and washed with ether. The aqueous layerwas then acidified and extracted with chloroform. The extract was washedwith water, dried over magnesium sulfate and concentrated under reducedpressure to obtain a faint yellow solid. It was purified according tosilica gel column chromatography (ethyl acetate/hexane=2:8) to obtain2.83 g of the intended compound in the form of white crystals.

mp.; 98°-99° C.

¹ H-NMR (90 MHz, CDCl₃) δ; 0.88 (t, J=7 Hz, 3H), 1.60-2.12 (m, 2H), 2.24(s, 3H), 2.96 and 3.08 (ABq, J=14 Hz, 2H), 4.26 (dd, J=9 Hz, 7 Hz, 1H),5.92 (s, 2H), 6.62 (s, 1H), 6.98 (s, 1H)

EXAMPLE 8 Sodium[{1-(6-methyl-1,3-benzodioxol-5-yl)-1-propyl}thio]-acetate ##STR184##

2.9 g of the intended compound in the form of white crystals wasobtained from 2.83 g of[{1-(6-methyl-1,3-benzodioxol-5-yl)-1-propyl}thio]acetic acid in thesame manner as that of Example 2.

mp.; 215°-216° C. (dec.)

¹ H-NMR (400 MHz, DMSO-d₆) δ; 0.78 (t, J=7 Hz, 3H), 1.62-1.69 (m, 1H),1.78-1.86 (m, 1H), 2.21 (s, 3H), 2.71 and 2.73 (ABq, J=13.0 Hz, 2H),4.07 (dd, J=9.2 Hz, 5.9 Hz, 1H), 5.93 (m, 2H), 6.69 (s, 1H), 6.86 (s,1H)

MS (FAB) m/z; 291 (MH⁻)

EXAMPLE 9Ethyl-[{1-(6-ethyl-1,3-benzodioxol-5-yl)-1-propyl}thio]-acetate##STR185##

3.9 g of 1-(6-ethyl-1,3-benzodioxol-5-yl)-1-propanol, 0.1 g ofp-toluenesulfonic acid and 3.35 g of ethyl mercaptoacetate weredissolved in 80 ml of benzene. The solution was heated under reflux for12 h while water was removed. Water was added thereto. After extractionwith benzene followed by drying over magnesium sulfate and concentrationunder reduced pressure, the product was purified according to silica gelcolumn chromatography (ethyl acetate/hexane=1:9) to obtain 4.0 g of theintended compound in the form of a colorless, transparent oil.

¹ H-NMR (90 MHz, CDCl₃) δ; 0.92 (t, J=7 Hz, 3H), 1.16 (t, J=7 Hz, 3H),1.26 (t, J=7 Hz, 3H), 1.50-2.12 (m, 2H), 2.44-2.80 (m, 2H), 2.96 and3.08 (ABq, J=14 Hz, 2H), 4.16 (q, J=7 Hz, 2H), 4.24 (dd, J=9 Hz, 7 Hz,1H), 5.92 (s, 2H), 6.64 (s, 1H), 7.00 (s, 1H)

EXAMPLE 10 [{1-(6-Ethyl-1,3-benzodioxol-5-yl)-1-propyl}thio]acetic Acid##STR186##

4.0 g of ethyl [{1-(6-ethyl-1,3-benzodioxol-5-yl)-1-propyl}thio]acetateand 2.6 g of sodium hydroxide were dissolved in a mixture of 20 ml ofwater and 20 ml of ethanol. The solution was heated under reflux for 2h. Ethanol was distilled off and the residue was washed with ether. Theaqueous layer was acidified and extracted with chloroform. The extractwas washed with water, dried over magnesium sulfate and concentratedunder reduced pressure. The residue was purified according to silica gelcolumn chromatography (ethyl acetate/hexane=2:8) to obtain 2.8 g of theintended compound in the form of white crystals.

mp.; 88°-89° C.

¹ H-NMR (90 MHz, CDCl₃) δ; 0.92 (t, J=7 Hz, 3H), 1.16 (t, J=7 Hz, 3 H),1.56-2.12 (m, 2H), 2.24-2.76 (m, 2H), 2.95 and 3.08 (ABq, J=16 Hz, 2H),4.20 (t, J=7 Hz, 1H), 5.88 (s, 2H), 6.58 (s, 1H), 6.90 (s, 1H), 9.72(bs, 1H)

EXAMPLE 11 Sodium[{1-(6-ethyl-1,3-benzodioxol-5-yl)-1-propyl}thio]-acetate ##STR187##

3.0 g of the intended compound in the form of white crystals wasobtained from 2.83 g of[{1-(6-ethyl-1,3-benzodioxol-5-yl)-1-propyl}thio]acetic acid in the samemanner as that of Example 2.

mp.; 221°-223° C. (dec.)

¹ H-NMR (400 MHz, DMSO-d₆) δ; 0.79 (t, J=7 Hz, 3H), 1.09 (t, J=7 Hz,3H), 1.63-1.70 (m, 1H), 1.80-1.88 (m, 1H), 2.47-2.56 (m, 1H), 2.60-2.67(m, 1H), 2.73 and 2.77 (ABq, J=13.9 Hz, 2H), 4.06 (dd, J=8.4 Hz, 6.2 Hz,1H), 5.93 (m, 2H), 6.69 (s, 1H), 6.87 (s, 1H)

MS (FAB) m/z; 305 (MH⁻)

EXAMPLE 12 [{(6-Methyl-1,3-benzodioxol-5-yl)methyl}thio]acetic Acid##STR188##

A suspension of 6.0 g of 5-chloromethyl-6-methyl-1,3-benzodioxole, 6.0 gof mercaptoacetic acid and 6.5 g of sodium hydroxide in 130 ml of 50%hydrous ethanol was heated under reflux for 1 h. The reaction mixturewas concentrated. Water was added thereto and the mixture was washedwith ethyl acetate. The aqueous layer was acidified with 1N hydrochloricacid. After extraction with chloroform, the extract was dried overmagnesium sulfate. The solvent was distilled off and the product wasisolated according to silica gel column chromatography (chloroform). Thecrystals thus obtained were recrystallized from diisopropyl ether toobtain 1.6 g of the intended compound in the form of white crystals.

mp.; 90°-92° C.

¹ H-NMR (90 Hz, CDCl₃) δ; 2.30 (s, 3H), 3.14 (s, 2H), 3.76 (s, 2H), 5.86(s, 2H), 6.60 (s, 1H), 6.70 (s, 1H)

EXAMPLE 13 Sodium [{(6-methyl-1,3-benzodioxol-5-yl)methyl}thio]acetate##STR189##

1.7 g of the intended compound in the form of white crystals wasobtained from 1.6 g of[{(6-methyl-1,3-benzodioxol-5-yl)methyl}thio]acetic acid in the samemanner as that of Example 2.

mp.; 214°-215° C. (dec.)

¹ H-NMR (400 MHz, DMSO-d₆) δ; 2.23 (s, 3H), 2.85 (s, 2H), 3.63 (s, 2H),5.93 (s, 2H), 6.73 (s, 1H), 6.81 (s, 1H)

MS (FAB, Neg) m/z; 239 (M-Na⁻)

EXAMPLE 14 {(5,6-Methylenedioxyindan-1-yl)thio}acetic Acid ##STR190##

0.94 g of 5,6-methylenedioxyindan-1-yl, 0.98 g of mercaptoacetic acidand a catalytic amount of D-10-camphorsulfonic acid were heated in 30 mlof benzene under reflux for 30 min. The reaction mixture was washed withwater and extracted with a 1N aqueous sodium hydroxide solution. Theaqueous layer was acidified with 1N hydrochloric acid and extracted withchloroform. The organic layer was dried over magnesium sulfate. Thesolvent was distilled off and the product was isolated according tosilica gel column chromatography (chloroform) to obtain 1.14 g of theintended compound in the form of faint brown oil.

¹ H-NMR (90 MHz, CDCl₃) δ; 2.07-3.09 (m, 4H), 3.22 (s, 2H), 4.37 (m,1H), 5.88 (s, 2H), 6.61 (s, 1H), 6.77 (s, 1H) 9.72 (m, 1H)

EXAMPLE 15 Sodium {(5,6-methylenedioxyindan-1-yl)thio}acetate ##STR191##

2.3 g of the intended compound in the form of white crystals wasobtained from 2.4 g of {(5,6-methylenedioxyindan-1-yl)thio}acetic acidin the same manner as that of Example 2.

mp.; 120°-224° C. (dec.)

¹ H-NMR (400 MHz, DMSO-d₆) δ; 2.01 (m, 1H), 2.39 (m, 1H), 2.67 (ddd,J=15.4 Hz, 8.4 Hz, 4.4 Hz, 1H), 2.84 (m, 1H), 2.89, 2.89 and 2.94 (ABq,J=13.6 Hz, 2H), 4.28 (dd, J=7.3 Hz, 4.0 Hz, 1H), 5.96 (m, 2H), 6.76 (s,1H), 6.84 (s, 1H)

MS (FAB, Neg) m/z; 251 (M-Na⁻)

EXAMPLE 16 {(6,7-Methylenedioxytetralin-1-yl)thio}acetic Acid ##STR192##

1.2 g of 6,7-methylenedioxy-1-tetralone was added to a suspension of 0.2g of lithium aluminum hydride in 20 ml of tetrahydrofuran under coolingwith ice. The mixture was stirred at room temperature overnight andcooled with ice/water. 0.2 ml of water, then 0.2 ml of a 15% aqueoussodium hydroxide solution and finally 0.6 ml of water were addedthereto. Insoluble substances were removed by filtration. The filtratewas concentrated to obtain a crystalline residue. 1.1 g ofmercaptoacetic acid and a catalytic amount of D-10-camphosulfonic acidwere added to the residue and the mixture was heated in 30 ml of benzeneunder reflux for 1 h. The reaction mixture was washed with water. Afterextraction with a 1N aqueous sodium hydroxide solution, the aqueouslayer was acidified with 1N hydrochloric acid. After extraction withchloroform, the extract was dried over magnesium sulfate and the solventwas distilled off. The crystalline residue thus obtained was treatedaccording to silica gel column chromatography (chloroform) to obtain 1.4g of the intended compound in the form of white crystals.

mp.; 138°-139° C.

¹ H-NMR (90 MHz, CDCl₃) δ; 1.6-2.2 (m, 4H), 2.65 (m, 2H), 3.20 and 3.34(ABq, J=16 Hz, 2H), 4.18 (m, 1H), 5.83 (s, 2H), 6.45 (s, 1H), 6.79 (s,1H)

EXAMPLE 17 Sodium {(6,7-methylenedioxytetraolin-1-yl)thio}acetate##STR193##

1.3 g of the intended compound in the form of white crystals wasobtained from 1.3 g of {(6,7-methylenedioxytetralin-1-yl)thio}aceticacid in the same manner as that of Example 2.

mp.; 180°-184° C. (dec.)

¹ H-NMR (400 MHz, DMSO-d₆) δ; 1.63 (m, 1H), 1.85 (m, 1H), 1.95 (m, 2H),2.59 (m, 2H), 2.89 and 3.04 (ABq, J=13.9 Hz, 2H), 4.18 (m, 1H), 5.91 (m,2H), 6.55 (s, 1H), 6.93 (s, 1H)

MS (FAB) m/z; 289 (MH⁻)

EXAMPLE 18 [{1-(6-Methyl-1,3-benzodioxol-5-yl)ethyl}sulfinyl]acetic Acid##STR194##

1.7 g of 80% m-chloroperbenzoic acid was added to a solution of 2.0 g of[{1-(6-methyl-1,3-benzodioxol-5-yl)ethyl}thio]acetic acid in 40 ml ofchloroform under cooling with ice. The mixture was stirred at roomtemperature overnight and a crystalline insoluble matter was recoveredby filtration and washed with ether to obtain 0.24 g of the intendedcompound (as a single diastereomer) in the form of white crystals.

mp.; 129°130° C. (dec.)

¹ H-NMR (90 MHz, DMSO-d₆) δ; 1.53 (d, J=7 Hz, 3H), 2.23 (s, 3H), 3.13and 3.54 (ABq, J=14 Hz, 2H), 4.26 (q, J=7 Hz, 1H), 5.92 (s, 2H), 6.72(s, 1H), 6.86 (s, 1H)

The filtrate obtained by the above-mentioned treatment was concentratedto obtain a crystalline residue, which was washed with benzene. Thewashing was concentrated to obtain a crystalline residue, which waswashed with ether to obtain 1.4 g of the intended compound (as the otherdiastereomer) in the form of white crystals.

mp.; 111°-112° C. (dec.)

¹ H-NMR (90 MHz, DMSO-d₆) δ; 1.52 (d, J=7 Hz, 3H), 2.26 (s, 3H), 3.51and 3.60 (ABq, J=14 Hz, 2H), 4.27 (q, J=7 Hz, 1H), 5.92 (s, 2H), 6.73(s, 3H)

EXAMPLE 19 [{1-(1,3-Benzodioxol-5-yl)-1-butyl}sulfinyl]acetic Acid##STR195##

2.0 g of the intended compound (as a diastereomer mixture of 3:1 asdetermined by NMR) in the form of a colorless oil was obtained from 2.9g of [{1-(1,3-benzodioxol-5-yl)-1-butyl}thio]acetic acid in the samemanner as that of Example 18.

¹ H-NMR (400 MHz, DMSO-d₆) δ; 0.86 (t, J=7.3 Hz, 3H×3/4), 0.88 (t, J=7.6Hz, 3H×1/4), 1.14-1.33 (m, 2H), 1.80-2.07 (m, 2H), 2.89 and 3.55 (ABq,J=14.4 Hz, 2H×1/4), 3.40 and 3.43 (ABq, J=14.3 Hz, 2H×3/4), 3.85 (dd,J=9.2 Hz, 7.0 Hz, 1H×1/4), 4.04 (dd, J=11.9 Hz, 3.9 Hz, 1H×3/4), 6.02(s, 2H), 6.74-6.95 (m, 3H)

EXAMPLE 20 [{1-(6-Methyl-1,3-benzodioxol-5-yl)ethyl}sulfonyl]acetic Acid##STR196##

3.4 g of 80% m-chloroperbenzoic acid was added to a solution of 2.0 g of[{1-(6-methyl-1,3-benzodioxol-5-yl)ethyl}thio]acetic acid under coolingwith ice. The mixture was stirred at room temperature overnight. Benzenewas added thereto and crystals thus formed were recovered by filtration.The crystals were dissolved in ethyl acetate and an insoluble substancewas filtered out. The filtrate was concentrated and a crystallineresidue thus formed was washed with ether to obtain 0.9 g of theintended compound in the form of white crystals.

mp.; 143°-144° C. (dec.)

¹ H-NMR (90 MHz, DMSO-d₆) δ; 1.62 (d, J=7 Hz, 3H), 2.27 (s, 3H), 3.96and 4.36 (ABq, J=15 Hz, 2H), 4.92 (q, J=7 Hz, 1H), 5.94 (s, 2H), 6.74(s, 1H), 6.87 (s, 1H)

COMPOUND GROUP (I-b) EXAMPLE 1 (COMPOUND 1)2-(1,3-Benzodioxol-5-yl)ethanethiol ##STR197##

750 g of 5-(2-bromoethyl)-1,3-benzodioxole was dissolved in 1 l ofethanol. 312 g of thiourea was added to the solution and the mixture washeated under reflux on a boiling water bath for 2 h. The reactionmixture was cooled. A solution of 300 g of sodium hydroxide in 1 l ofwater was added thereto and the mixture was heated under reflux on aboiling water bath for 45 min. After cooling, 3 l of water was addedthereto and the product was extracted with 5 l of ethyl acetate. Theextract was washed with dilute hydrochloric acid. It was then washedwith water until the washing became substantially neutral and dried overanhydrous sodium sulfate. The solvent was distilled off at 40° C. toobtain about 570 g of a faint yellow oil. It was purified according tocolumn chromatography with about 3 kg of silica gel (hexane:benzene=2:1)to obtain 310 g of the intended compound in the form of a colorless oil.

NMR (90 MHz, CDCl₃) δ; 1.36 (m, 1H), 2.6-2.9 (m, 4H), 5.87 (s, 2H),6.50-6.74 (m, 3H)

EXAMPLE 2 (COMPOUND 21) Sodium2-Amino-3-[{2-(1,3-benzodioxol-5-yl)ethyl}thio]propionate ##STR198##

406 g of L-cysteine.HCl.H₂ O was suspended in a mixture of 1 l of waterand 500 ml of ethanol. A solution of 370 g of sodium hydroxide in 1.5 lof water was added to the suspension. 527 g of5-ethenyl-1,3-benzodioxole and then 500 ml of ethanol were added theretoand the mixture was heated under reflux for 2.5 h to conduct thereaction. Ethanol was distilled off under reduced pressure and theresidue was filtered. The filtrate was acidified with acetic acid toform colorless crystals, which were recovered by filtration andrecrystallized from 3 l of water to obtain 250 g of2-amino-3-[{2-(1,3-benzodioxol-5-yl)ethyl}thio]propionic acid in theform of colorless needles.

The crystals were dissolved in a solution of 37 g of sodium hydroxide in1 l of water. The solution was filtered and the filtrate wasconcentrated into about a half volume. 1.5 l of ethanol was addedthereto to recrystallize the product. 100 g of the intended product wasobtained in the form of colorless crystals.

m.p.: 170° to 172° C.

NMR (400 MHz, DMSO-d₆) δ; 2.64-2.74 (m, 5H), 2.91 (dd, J=12.8 Hz, 3.7Hz, 1H), 3.01 (m, 1H), 3.3 (m, 2H), 5.95 (s, 2H), 6.68 (dd, J=8.1 Hz,1.8 Hz, 1H), 6.79 (d, J=8.1 Hz, 1H), 6.83 (d, J=1.8 Hz, 1H)

MS (FAB) m/z; 314 (M⁺ +Na), 292 (M⁺ +1)

Elementary analysis for C₁₂ H₁₄ NO₄ SNa:

    ______________________________________                                                   C         H      N                                                 ______________________________________                                        calculated (%)                                                                             49.48       4.84   4.81                                          found (%)    49.58       4.91   4.91                                          ______________________________________                                    

EXAMPLE 3 (COMPOUND 8) Sodium[{2-(1,3-benzodioxol-5-yl)ethyl}thio]acetate ##STR199##

100 g of 2-(1,3-benzodioxol-5-yl)ethanethiol and 75.1 g of bromoaceticacid were dissolved in 1 l of ethanol. A solution of 44 g of sodiumhydroxide in 125 ml of water and then 2 l of ethanol were added thereto.The mixture was heated under reflux for 3 h. The reaction mixture wasconcentrated under reduced pressure. 2.5 l of water was added thereto.The mixture was made alkaline with a 1N sodium hydroxide solution,washed with 35% hydrochloric acid, extracted with ethyl acetate, washedwith water four times and dried over sodium sulfate. The solvent wasdistilled off under reduced pressure to obtain 121 g of[{2-(1,3-benzodioxol-5-yl)ethyl}thio]acetic acid in the form of a faintyellow oil.

NMR (90 MHz, CDCl₃) δ; 2.80 (s, 4H), 3.20 (s, 2H), 5.85 (s, 2H),6.44-6.74 (m, 3H), 10.24 (bs, 1H)

MS (EI) m/z; 240 (M⁺), 135 (Base)

A solution of 20.27 g of sodium hydroxide in 200 ml of water was addedto the oily product to obtain a solution. After recrystallization fromdilute ethanol, 102.5 g of the intended compound was obtained in theform of colorless crystals.

m.p.: 224° to 226° C.

NMR (400 MHz, DMSO-d₆) δ; 2.69 (m, 4H), 2.95 (s, 2H), 5.95 (s, 2H), 6.66(dd, J=7.7 Hz, 1.5 Hz, 1H), 6.79 (d, J=7.7 Hz, 1H), 6.81 (d, J=1.5 Hz,1H)

MS (FAB) m/z; 285 (M⁺ +Na, 263 (M⁺ +1)

Elementary analysis for C₁₁ H₁₁ O₄ SNa:

    ______________________________________                                                         C    H                                                       ______________________________________                                        calculated (%)     50.38  4.23                                                found (%)          50.27  4.31                                                ______________________________________                                    

EXAMPLE 4 (COMPOUND 17)3-[{2-(1,3-Benzodioxol-5-yl)ethyl}thio]propionamide ##STR200##

5 g of 2-(1,3-benzodioxol-5-yl)ethanethiol and 4 g of acrylamide weredissolved in 100 ml of ethanol and the solution was heated under refluxto conduct the reaction for 20 h. The reaction mixture was cooled withice. 100 ml of ethanol was added thereto and crystals thus formed wererecovered by filtration to obtain 4.2 g of the intended compound in theform of colorless needles.

m.p.: 103° to 104° C.

NMR (90 MHz, CDCl₃) δ; 2.50 (m, 2H), 2.89 (s, 4H), 2.73-2.93 (m, 2H),5.6 (br, s, 2H), 5.91 (s, 2H), 6.68 (m, 3H)

MS (EI) m/z; 253 (M⁺), 149, 136 (Base)

EXAMPLE 5 (COMPOUND 25) Ethyl[{2-(1,3-benzodioxol-5-yl)ethyl}thio]acetate ##STR201##

3.24 g of ethyl thioglycolate was added to 6 g of5-ethenyl-1,3-benzodioxole and the mixture was stirred at roomtemperature for 14 h. The reaction product was purified according tosilica gel column chromatography (benzene:ethyl acetate=40:1) to obtain5 g of the intended compound in the form of a colorless oil.

NMR (90 MHz, CDCl₃) δ; 1.27 (t, J=7 Hz, 3H), 2.80 (s, 4H), 3.18 (s, 2H),4.15 (q, J=7 Hz, 2H), 5.86 (s, 2H), 6.62 (m, 3H)

MS (EI) m/z; 268 (M⁺), 149 (Base)

EXAMPLE 6 (COMPOUND 26) 5-[2-(Methylsulfinyl)ethyl]-1,3-benzodioxole##STR202##

3 g of 5-{2-(methylthio)ethyl}-1,3-benzodioxole was dissolved in 100 mlof chloroform. An equimolar amount of m-chloroperbenzoic acid was addedto the solution under stirring under reflux with dry ice/alcohol toconduct the reaction for 1 h. 300 ml of chloroform and 300 ml of waterwere added thereto and then sodium carbonate was added to the mixtureuntil the aqueous layer became alkaline. After separation of the layers,the chloroform layer was washed with water twice and dried over sodiumsulfate. The solvent was distilled off under reduced pressure. The oilyproduct was purified according to silica gel column chromatography(chloroform:methanol=20:1) to obtain 1.6 g of the intended compound inthe form of a colorless oil.

NMR (90 MHz, CDCl₃) δ; 2.55 (s, 3H), 2.74-3.12 (m, 4H), 5.87 (s, 2H),6.64 (m, 3H)

MS (EI) m/z; 212 (M⁺), 196, 148 (Base)

EXAMPLE 7 (COMPOUND 28) 5-{2-(Methylsulfonyl)ethyl}-1,3-benzodioxole##STR203##

3.5 g of 5-{2-(methylthio)ethyl}-1,3-benzodioxole was dissolved in 100ml of chloroform. 8.8 g of m-chloroperbenzoic acid was added to thesolution under cooling with ice/water to conduct the reaction for 2 h.300 ml of chloroform and 300 ml of water were added thereto and thensodium carbonate was added to the mixture until the aqueous layer becamealkaline. After separation of the layers, the chloroform layer waswashed with water twice and dried over sodium sulfate. The solvent wasdistilled off under reduced pressure. After recrystallization from ethylacetate/isopropyl ether, 3 g of the intended compound was obtained inthe form of colorless needles.

NMR (90 MHz, CDCl₃) δ; 2.80 (s, 3H), 2.93-3.36 (m, 4H), 5.88 (s, 2H),6.65 (m, 3H)

MS (EI) m/z; 228 (M⁺), 148 (Base)

EXAMPLE 8 (COMPOUND 22) [{2-(1,3-Benzodioxol-5-yl)ethyl}thio]ethylNicotinate ##STR204##

4 g of [{2-(1,3-benzodioxol-5-yl)ethyl}thio]ethanol prepared in the samemanner as that of Example 2 was dissolved in 20 ml of pyridine. 50 ml ofbenzene was added to the solution. 4.7 g of nicotinic chloridehydrochloride was added thereto under stirring and the mixture washeated on a boiling water bath for 2 h. The reaction mixture was pouredinto ice/water. 100 ml of water and sodium hydrogen-carbonate were addedthereto to make it weakly alkaline. After extraction with ethyl acetate,the ethyl acetate layer was washed with water four times and dried oversodium sulfate. The solvent was distilled off and the residue waspurified according to silica gel column chromatography (benzene:ethylacetate=3:1) to obtain 2 g of the intended compound in the form of acolorless oil.

NMR (90 MHz, CDCl₃) δ; 2.80 (s, 4H), 2.85 (t, J=7 Hz, 2H), 4.44 (t, J=7Hz, 2H), 5.86 (s, 2H), 6.61 (m, 3H), 7.31 (m, 1H), 8.20 (m, 1H), 8.69(m, 1H), 9.13 (m, 1H)

MS (EI) m/z; 331 (M⁺, Base), 148

EXAMPLE 9 (COMPOUND 23)N-[2-{(1,3-Benzodioxol-5-yl)ethyl}thio]-1-oxoethyl]aminoacetic Acid##STR205##

5.3 g of [{2-(1,3-benzodioxol-5-yl)ethyl}thio]acetic acid prepared inExample 2 was dissolved in 20 ml of benzene. 6.43 ml of thionyl chloridewas added to the solution and the mixture was heated under reflux for 2h to conduct the reaction. The solvent was distilled off under reducedpressure. 3 g of glycine was added to a solution of 1.6 g of sodiumhydroxide in 10 ml of water. The reaction product obtained as above wasadded thereto under stirring under cooling with ice/water. The mixturewas stirred at about 10° C. for 15 min and then the reaction wasconducted at room temperature for 2 h. Water was added to the reactionmixture, which was acidified with concentrated hydrochloric acid. Theprecipitates thus formed were recovered by filtration, washed with waterand recrystallized repeatedly from dilute ethanol to obtain 3 g of theintended compound in the form of colorless needles.

m.p.: 121.5° to 122.5° C.

NMR (90 MHz, CDCl₃ --CD₃ OD) δ; 2.84 (s, 4H), 3.26 (s, 2H), 3.99 (s,2H), 5.92 (s, 2H), 6.71 (m, 3H), 7.54 (s, 1H)

MS (EI) m/z; 297 (M⁺), 149 (Base), 148

In the following Examples 10 to 27, compounds of the following generalformula (I') wherein R was a group shown below were prepared.

Preparation processes A, B, C, D and E were the same as those ofExamples 2, 3, 4, 5 and 9, respectively. ##STR206##

EXAMPLE 10 (COMPOUND 2) R=--CH₂ CH₂ CH₃ (Preparation Process B)

NMR (90 MHz, CDCl₃) δ; 0.98 (t, J=7 Hz, 3H), 1.4-1.8 (m, 2H), 2.51 (t,J=7 Hz, 2H), 2.75 (s, 4H), 5.91 (s, 2H), 6.7 (m, 3H)

MS (EI) m/z; 224 (M⁺), 148, 135, 77 (Base)

EXAMPLE 11 (COMPOUND 3) R=--CH₂ CH₂ OH (Preparation Process B)

NMR (90 MHz, CDCl₃) δ; 2.72 (t, J=6 Hz, 2H), 2.78 (s, 4H), 3.72 (q, J=6Hz, 2H), 5.92 (s, 2H), 6.6-6.8 (m, 3H)

MS (FD) m/z; 226 (M⁺)

Elementary analysis for C₁₁ H₁₄ O₃ S:

    ______________________________________                                                   C         H      S                                                 ______________________________________                                        calculated (%)                                                                             58.39       6.24   14.17                                         found (%)    58.61       6.22   13.83                                         ______________________________________                                    

EXAMPLE 12 (COMPOUND 4) R=--(CH₂)₃ OH (Preparation Process B)

NMR (90 MHz, CDCl₃) δ; 1.59 (m, 1H), 1.85 (m, 2H), 2.66 (t, J=7 Hz, 2H),2.78 (s, 4H), 3.76 (m, 2H), 5.93 (s, 3H), 6.70 (m, 3H)

MS (EI) m/z; 240 (M⁺), 148 (Base), 135

EXAMPLE 13 (COMPOUND 5) ##STR207##

NMR (90 MHz, CDCl₃) δ; 2.02 (t, J=6 Hz, 1H), 2.6-2.9 (m, 3H), 2.80 (s,4H), 3.4-3.9 (m, 3H), 5.94 (s, 2H), 6.70 (m, 3H)

MS (EI) m/z; 256 (M⁺), 149, 135, 91, 77, 65 (Base)

EXAMPLE 14 (COMPOUND 6) R=--CH₂ CH₂ OCH₃ (Preparation Process B)

NMR (90 MHz, CDCl₃) δ; 2.68 (t, J=7 Hz, 2H), 2.76 (s, 4H, 3.33 (s, 3H),3.52 (t, J=7 Hz, 2H), 5.87 (s, 2H), 6.62 (m, 3H)

MS (EI) m/z; 240 (M⁺), 148, 135, 77 (Base)

EXAMPLE 15 (COMPOUND 7) ##STR208##

NMR (90 MHz, CDCl₃) δ; 1.5-2.2 (m, 4H), 2.46 (m, 2H), 2.79 (s, 4H),2.6-3.1 (m, 3H), 5.91 (s, 2H), 6.68 (m, 3H)

MS (EI) m/z; 266 (M⁺), 149 (Base)

EXAMPLE 16 (COMPOUND 9) R=--CH₂ CH₂ COOH (Free Form) (Process A, B or D)

m.p.: 63.0° to 64.0° C.

NMR (90 MHz, CDCl₃) δ; 2.77 (m, 4H), 2.50-2.90 (m, 4H), 5.91 (s, 2H),6.67 (m, 3H), 8.0 (br,s1H)

MS (EI) m/z; 254 (M⁺, Base), 148, 135

R=--CH₂ CH₂ COONa (Preparation Process A, B or D)

m.p.: 187° to 189° C.

NMR (400 MHz, d₆ -DMSO) δ; 2.11 (m, 2H), 2.62-2.74 (m, 6H), 5.95 (s,2H), 6.68 (dd, J=7.7 Hz, 1.5 Hz, 1H), 6.79 (d, J=7.7 Hz, 1H), 6.82 (d,J=1.5 Hz, 1H)

MS (FAB) m/z; 299 (M⁺ +Na), 277 (M⁺ +1)

Elementary analysis for C₁₂ H₁₃ O₄ SNa;

    ______________________________________                                                         C    H                                                       ______________________________________                                        calculated (%)     52.17  4.74                                                found (%)          52.15  4.80                                                ______________________________________                                    

EXAMPLE 17 (COMPOUND 10) R=--(CH₂)₃ COONa (Preparation Process B)

NMR (90 MHz, D₂ O) δ; 1.90 (m, 2H), 2.30 (t, J=7 Hz, 2H), 2.59 (t, J=7Hz, 2H), 2.85 (s, 4H), 5.94 (s, 2H), 6.80 (m, 3H)

MS (FAB) m/z; 313 (M⁺ +Na), 291 (M⁺ +1)

EXAMPLE 18 (COMPOUND 1) R=--(CH₂)₄ COONa (Preparation Process B )

NMR (90 MHz, CDCl₃) δ; 1.69 (m, 4H), 2.46 (m, 4H), 2.74 (s, 4H), 5.87(s, 3H), 6.61 (m, 3H), 7.28 (br, 1H)

MS (Na salt) (FAB) m/z; 327 (M⁺ +Na), 305 (M⁺ +1)

EXAMPLE 19 (COMPOUND 12) R=--(CH₂)₅ COONa (Preparation Process B)

m.p.: 248° to 251° C.

NMR (90 MHz, D₂ O) δ; 1.16-1.70 (m, 6H), 2.17 (m, 2H), 2.45 (m, 2H),2.66 (s, 4H), 5.82 (s, 2H), 6.66 (m, 3H)

ms (FAB) m/z; 341 (M⁺ +Na), 319 (M⁺ +1)

EXAMPLE 20 (COMPOUND 13) ##STR209##

NMR (90 MHz, CDCl₃) δ; 1.35 (d, J=7 Hz, 3H), 2.57 (m, 2H), 2.76 (s, 4H),3.18 (m, 1H), 5.86 (s, 2H), 6.62 (m, 3H), 7.2 (br, 1H) ##STR210##

m.p.: 126° to 128.5° C.

NMR (400 MHz, DMSO-d₆) δ; 1.18 (d, J=6.6 Hz, 3H), 1.88 (dd, J=14.7 Hz,9.9 Hz, 1H), 2.20 (dd, J=14.7 Hz, 4.4 Hz, 1H), 2.69 (m, 4H), 3.14 (m,1H), 5.95 (s, 2H) 6.68 (dd, J=8.0 Hz, 1.8 Hz, 1H), 6.79 (d, J=8.0 Hz,1H), 6.82 (d, J=1.8 Hz, 1H)

MS (FAB) m/z; 313 (M⁺ +Na), 291 (M⁺ +1)

Elementary analysis for C₁₃ H₁₅ O₄ SNa.3/4H₂ O

    ______________________________________                                                         C    H                                                       ______________________________________                                        calculated (%)     51.39  5.47                                                found (%)          51.22  5.52                                                ______________________________________                                    

EXAMPLE 21 (COMPOUND 14) ##STR211##

m.p.: 139° to 140° C.

NMR (90 MHz, DMSO-d₆) δ; 2.77 (br, s, 4H), 3.28 (br, s, 2H), 3.50 (m,1H), 5.88 (s, 2H), 6.69 (m, 3H)

MS (EI) m/z; 298 (M⁺), 280, 148 (Base)

EXAMPLE 22 (COMPOUND 15) ##STR212##

NMR (90 MHz, D₂ O) δ; 1.40 (d, J=7 Hz, 3H), 2.36 (s, 4H), 3.43 (q, J=7Hz, 1H), 5.93 (s, 2H), 6.80 (m, 3H)

MS (FAB) m/z; 299 (M⁺ +Na), 277 (M⁺ +1)

EXAMPLE 23 (COMPOUND 16) R=--CH₂ CONH₂ (Preparation Process B)

m.p.: 93.5° to 94.5° C.

NMR (90 MHz, CDCl₃) δ; 2.78 (s, 4H), 3.18 (s, 2H), 5.6-6.9 (br, s, 2H),5.86 (s, 2H), 6.61 (m, 3H)

MS (El) m/z; 229 (M⁺), 148 (Base)

Elementary analysis for C₁₁ H₁₃ O₃ NS:

    ______________________________________                                                    C    H         N      S                                           ______________________________________                                        calculated (%)                                                                              55.21  5.48      5.85 13.40                                     found (%)     55.38  5.42      5.82 13.34                                     ______________________________________                                    

EXAMPLE 24 (COMPOUND 18) ##STR213##

NMR (90 MHz, CDCl₃) δ; 1.17 (q, J=7 Hz, 6H), 2.86 (s, 2H), 3.28 (s, 2H),3.37 (q, J=7 Hz, 2H), 3.39 (q, J=7 Hz, 2H), 5.92 (s, 2H), 6.72 (m, 3H)

MS (EI) m/z; 295 (M⁺), 148 (Base)

EXAMPLE 25 (COMPOUND 19) ##STR214##

NMR (90 MHz, CDCl₃) δ; 2.44-2.85 (m, 4H), 2.75 (s, 4H), 2.92 (s, 3H),2.96 (s, 3H), 5.84 (s, 2H), 6.61 (m, 3H)

MS (EI) m/z; 281 (M⁺), 149 (Base)

EXAMPLE 26 (COMPOUND 20) ##STR215##

m.p.: 146° to 148° C.

NMR (90 MHz, CDCl₃) δ; 2.79 (s, 6H), 2.84 (s, 4H), 3.06 (m, 4H), 5.94(s, 2H), 6.72 (m, 3H)

MS (EI) m/z; 253 (M⁺), 149, 135, 105, 91 (Base)

EXAMPLE 27 (COMPOUND 24) ##STR216##

m.p. 152° to 153° C.

NMR (90 MHz, CDCl₃ --CD₃ OD) δ; 2.53 (m, 2H), 2.73-2.92 (m, 6H), 3.94(s, 2H), 5.90 (s, 2H), 6.69 (m, 3H), 7.58 (s, 1H)

MS (EI) m/z; 311 (M⁺), 149 (Base), 148

In the following Example 28, compounds of the following general formula(I") wherein R was a group shown below were prepared.

These compounds were prepared in the same manner as that of Example 6.##STR217##

EXAMPLE 28 (COMPOUND 27) R=--CH₂ CH₂ OH

m.p.: 107° to 108° C.

NMR (90 MHz, CDCl₃) δ; 2.8-3.3 (m, 7H), 4.18 (m, 2H), 5.94 (s, 2H), 6.72(m, 3H)

MS (FAB) m/z; 243 (M⁺ +1)

In the following Examples 29 to 32, compounds of the following generalformula (I'") wherein R was a group shown below were prepared.

These compounds were prepared in the same manner as that of Example 7.##STR218##

EXAMPLE 29 (COMPOUND 29) R=CH₂ CH₂ OH

m.p.: 78° to 80° C.

NMR (90 MHz, CDCl₃) δ; 2.37 (t, J=6 Hz, 1H), 2.9-3.5 (m, 6H), 4.12 (m,2H), 5.95 (s, 2H), 6.72 (m, 3H)

MS (EI) m/z; 258 (M⁺), 149, 119 (Base)

EXAMPLE 30 (COMPOUND 30) R=--CH₂ COOH

m.p.: 144.5° to 145° C.

NMR (90 MHz, DMSO-d₆ -CDCl₃) δ; 3.04 (m, 2H), 3.52 (m, 2H), 4.07 (s,2H), 5.3 (br, 1H), 5.95 (s, 2H), 6.86 (m, 3H)

MS (EI) m/z; 272 (M⁺), 148 (Base)

EXAMPLE 31 (COMPOUND 31) R=--CH₂ CH₂ COOH

m.p.: 176.5° to 177.5° C.

NMR (90 MHz, DMSO-d₆) δ; 2.60-3.10 (m, 4H), 3.24-3.50 (m, 4H), 5.98 (s,2H), 6.81 (m, 2H), 6.92 (m, 1H), 12.3 (br, 1H)

MS (EI) m/z; 286 (M⁺, Base)

EXAMPLE 32 (COMPOUND 32) R=--(CH₂)₃ COOH

m.p.: 153.5° to 155.5° C.

NMR (90 MHz, DMSO-d₆) δ; 1.95 (m, 2H), 2.40 (t, J=7 Hz, 2H), 2.80-3.46(m, 6H), 5.96 (s, 2H), 6.80 (m, 1H), 6.91 (m, 1H), 12.5 (br, 1H)

MS (EI) m/z; 300 (M⁺), 149 (Base), 148

COMPOUND GROUP (I-c) EXAMPLE 13-(6-Propyl-1,3-benzodioxole-5-yl)propionic Acid ##STR219## (1)Synthesis of 5-chloromethyl-6-propyl-1,3-benzodioxole ##STR220##

22 g of a 37% aqueous formaldehyde solution and 20 ml of ethyl acetatewere added to 10 ml of concentrated hydrochloric acid. The mixture washeated to 55° C. A solution of 10.9 g of 5-propyl-1,3-benzodioxole in100 ml of ethyl acetate was added dropwise to the mixture while hydrogenchloride gas was introduced thereinto. The mixture was stirred for 2 hand 45 min. 300 ml of ethyl acetate and 300 ml of water were addedthereto. The formed layers were separated. The ethyl acetate layer waswashed with water three times and dried over anhydrous sodium sulfate.The solvent was distilled off to obtain 16.1 of the crude intendedcompound in the form of a colorless oil.

¹ H-NMR (90 MHz, CDCl₃) δ; 0.99 (t, J=7.2 Hz, 3H), 1.36-1.86 (m, 2H),2.64 (t, J=7.2 Hz, 2H), 4.57 (s, 2H), 5.95 (s, 2H), 6.70 (s, 1H), 6.83(s, 1H)

(2) Synthesis of Diethyl (6-propyl-1,3-benzodioxole-5-yl)methylmalonate##STR221##

24.3 g of diethyl malonate, 42 g of potassium carbonate, 300 ml ofacetone and a catalytic amount of tetrabutylammonium bromide were addedto 16.1 g of crude 5-chloromethyl-6-propyl-1,3-benzodioxole and themixture was heated under reflux for 52 h. The reaction mixture wasfiltered and the residue was washed with acetone. The washing wascombined with the filtrate. The solvent was distilled off. 500 ml ofethyl acetate and 500 ml of water were added thereto and the layers thusformed were separated. The ethyl acetate layer was washed with waterthree times and dried over anhydrous sodium sulfate. The solvent wasdistilled off to obtain 16.5 g of the crude intended compound in theform of a colorless oil.

¹ H-NMR (90 MHz, CDCl₃) δ; 0.96 (t, J=7.2 Hz, 3H), 1.22 (t, 7.2 Hz, 6H),1.30-1.80 (m, 2H), 2.32-2.60 (m, 2H), 3.10 (d, J=7.2 Hz, 2H), 3.50 (t,J=7.2 Hz, 1H), 4.14 (q, J=7.2 Hz, 4H), 5.83 (s, 2H), 6.58 (s, 2H)

(3) Synthesis of (6-propyl-1,3-benzodioxole-5-yl)methylmalonate##STR222##

16.5 g of diethyl (6-propyl-1,3-benzodioxole-5-yl)methylmalonate wasdissolved in 150 ml of ethanol. 20 g of sodium hydroxide and 50 ml ofwater were added to the solution and the mixture was heated on a boilingwater bath for 30 min. The reaction mixture was concentrated. 300 ml ofethyl acetate and 300 ml of water were added thereto and the layers thusformed were separated. The aqueous layer was acidified with concentratedhydrochloric acid. After extraction with ethyl acetate, the ethylacetate layer was washed with water three times and then dried overanhydrous sodium sulfate. The solvent was distilled off to obtain 15.2 gof the intended compound in the form of a white powder.

¹ H-NMR (90 MHz, DMSO-d₆) δ; 0.91 (t, J=7.2 Hz, 3H), 1.31-1.66 (m, 2H),2.50 (t, J=7.2 Hz, 2H), 2.98 (d, J=7.2 Hz, 2H), 3.47 (t, J=7.2 Hz, 1H),5.94 (s, 2H), 6.74 (s, 2H), 12.7 (bs, 2H)

(4) Synthesis of 3-(6-propyl-1,3-benzodioxole-5-yl)propionic Acid##STR223##

10 g of (6-propyl-1,3-benzodioxole-5-yl)methylmalonic acid was heated at150° to 160° C. on an oil bath for 1 h. It was then purified accordingto silica gel column chromatography (chloroform/methanol=20:1) andrecrystallized from isopropyl ether to obtain 6.9 g of the intendedcompound in the form of colorless crystals.

¹ H-NMR (90 MHz, CDCl₃) δ; 0.95 (t, J=7.0 Hz, 3H), 1.28-1.80 (m, 2H),2.08-3.00 (m, 6H), 5.85 (s, 2H), 6.58 (s, 2H)

EXAMPLE 2 Sodium 3-(6-propyl-1,3-benzodioxole-5-yl)propionate ##STR224##

29.2 ml of a 1N aqueous sodium hydroxide solution and 100 ml of ethanolwere added to 6.9 g of 3-(6-propyl-1,3-benzodioxole-5-yl)propionic acidto obtain a solution. The solvent was distilled off and ether was addedto the residue. A precipitation thus formed was recovered by filtrationand dried to obtain 7.5 g of the intended compound in the form of acolorless powder.

m.p. (°C.); 213-216

¹ H-NMR (90 MHz, DMSO-d₆) δ; 0.90 (t, J=7.4 Hz, 3H), 1.20-2.71 (m, 2H),1.92-2.22 (m, 2H), 2.26-2.80 (m, 4H), 5.82 (s, 2H), 6.57 (s, 1H), 6.64(s, 1H)

MS (FAB) m/z; 281 (MNa⁻), 259 (MH⁻)

EXAMPLE 3 3-(6-Ethyl-1,3-benzodioxole-5-yl)propionic Acid ##STR225##

1.42 g of the intended compound in the form of colorless crystals wasobtained from 5.4 g of 5-ethyl-1,3-benzodioxole in the same manner asthat of Example 1.

¹ H-NMR (90 MHz, CDCl₃) δ; 1.20 (t, J=7 Hz, 3H), 2.32-3.08 (m, 6H), 5.84(s, 2H), 6.60 (s, 1H), 6.64 (s, 1H)

EXAMPLE 4 Sodium 3-(6-ethyl-1,3-benzodioxole-5-yl)propionate ##STR226##

1.53 g of the intended compound in the form of colorless crystals wasobtained from 1.42 g of 3-(6-ethyl-1,3-benzodioxole-5-yl)propionic acidin the same manner as that of Example 2.

m.p. (°C.); 202-204 (dec.)

¹ H-NMR (400 MHz, DMSO-d₆) δ; 1.10 (t, J=7 Hz, 3H), 2.06 (t, J=8 Hz,2H), 2.51 (q, J=7 Hz, 2H), 2.66 (t, J=8 Hz, 2H), 5.88 (s, 2H), 6.68 (s,1H), 6.71 (s, 1H)

MS (FAB) m/z; 245 (MH⁻)

EXAMPLE 5 3-(6-Methyl-1,3-benzodioxole-5-yl)propionic Acid ##STR227##

80 g of the intended compound in the form of colorless crystals wasobtained from 150 g of 5-methyl-1,3-benzodioxole in the same manner asthat of Example 1.

m.p. (°C.); 129-132

¹ H-NMR (90 MHz, CDCl₃) δ; 2.20 (s, 3H), 2.36-2.98 (m, 4H), 5.81 (s,2H), 6.56 (s, 2H), 11.24 (bs, 1H)

EXAMPLE 6 Sodium 3-(6-methyl-1,3-benzodioxole-5-yl)propionate ##STR228##

0.59 g of the intended compound in the form of a white powder wasobtained from 0.54 g of 3-(6-methyl-1,3-benzodioxole-5-yl)propionic acidin the same manner as that of Example 2.

m.p. (°C.); 209-212

¹ H-NMR (90 MHz, DMSO-d₆) δ; 2.54 (s, 3H), 1.86-2.84 (m, 4H), 5.80 (s,2H), 6.56 (s, 1H), 6.63 (s, 1H)

MS (FAB) m/z; 253 (MNa⁻), 231 (MH⁻)

EXAMPLE 7 3-(6-Methoxymethyl-1,3-benzodioxole-5-yl)propionic Acid##STR229##

1.6 g of 3-(6-acetoxymethyl-1,3-benzodioxole-5-yl)propionic acid wasdissolved in 100 ml of methanol. A catalytic amount of p-toluenesulfonicacid was added to the solution and the mixture was heated under refluxfor 4 h and 15 min. The solvent was distilled off from the reactionmixture. A solution of 1 g of sodium hydroxide in a mixture of 5 ml ofwater and 45 ml of ethanol was added to the residue and the mixture washeated under reflux for 20 min. The reaction mixture was concentrated.200 ml of ethyl acetate and 200 ml of water were added to theconcentrate. The mixture was acidified with concentrated hydrochloricacid. The layers thus formed were separated. The product was washed withwater three times and then dried over anhydrous sodium sulfate. Thesolvent was distilled off to obtain 1.25 g of the intended compound inthe form of a white powder.

¹ H-NMR (90 MHz, CDCl₃) δ; 2.24-3.10 (m, 4H), 3.34 (s, 3H), 4.33 (s,2H), 5.86 (s, 2H), 6.64 (s, 1H), 6.74 (s, 1H)

EXAMPLE 8 Sodium 3-(6-methoxymethyl-1,3-benzodioxole-5-yl)propionate##STR230##

1.3 g of the intended compound in the form of a white powder wasobtained from 1.25 g of3-(6-methoxymethyl-1,3-benzodioxole-5-yl)propionic acid in the samemanner as that of Example 2.

m.p. (°C.); 155-159

¹ H-NMR (90 MHz, DMSO-d₆) δ; 1.88-2.90 (m, 4H), 3.23 (s, 3H), 4.28 (s,2H), 5.87 (s, 2H), 6.71 (s, 1H), 6.74 (s, 1H)

MS (FAB) m/z; 283 (MNa⁻), 261 (MH⁻)

EXAMPLE 9 3-(6-Ethoxymethyl-1,3-benzodioxole-5-yl)propionic Acid##STR231##

0.6 g of metallic sodium was dissolved in 100 ml of ethanol. 2.0 g of3-(6-chloromethyl-1,3-benzodioxole-5-yl)propionic acid was added insmall portions to the solution. The mixture was heated at 50° C. for 2h. The solvent was distilled off and the residue was acidified with 1Nhydrochloric acid. After extraction with chloroform, the organic layerwas dried over magnesium sulfate. The solvent was distilled off. Afterseparation according to silica gel column chromatography (chloroform),0.73 g of the intended compound in the form of colorless crystals wasobtained.

m.p. (°C.); 97-98

¹ H-NMR (90 MHz, CDCl₃) δ; 1.23 (t, J=7 Hz, 3H), 2.61 (m, 2H), 2.91 (m,2H), 3.51 (q, J=7 Hz, 2H), 4.38 (s, 2H), 5.87 (s, 2H), 6.64 (s, 1H),6.76 (s, 1H)

EXAMPLE 10 Sodium 3-(6-ethoxymethyl-1,3-benzodioxole-5-yl)propionate##STR232##

0.7 g of the intended compound in the form of colorless crystals wasobtained from 0.71 g of3-(6-ethoxymethyl-1,3-benzodioxole-5-yl)propionic acid in the samemanner as that of Example 2.

m.p. (°C.); 165-182 (dec.)

¹ H-NMR (400 MHz, DMSO-d₆) δ; 1.13 (t, J=7.0 Hz, 3H), 2.07 (m, 2H), 2.68(m, 2H), 3.45 (q, J=7.0 Hz, 2H), 4.36 (s, 2H), 5.92 (s, 2H), 6.78 (s,1H), 6.81 (s, 1H)

MS (FAB) m/z; 297 (MNa⁻), 275 (MH⁻)

EXAMPLE 11 (5,6-Methylenedioxyindane-2-yl)carboxylic Acid ##STR233## (1)Synthesis of 5,6-Methylenedioxyindene ##STR234##

A solution of 10.8 g of 1-hydroxy-5,6-methylenedioxyindane and 15 ml ofacetic acid in 100 ml of toluene was heated under reflux for 4 h. Waterand a small amount of potassium carbonate were added to the reactionmixture. After extraction with ethyl acetate, the organic layer waswashed with water and an aqueous common salt solution and dried overmagnesium sulfate. The solvent was distilled off and the residue wastreated according to silica gel column chromatography(chloroform/hexane=1:3) to obtain 9.0 g of the intended compound in theform of colorless crystals.

m.p. (°C.); 85-86

¹ H-NMR (90 MHz, CDCl₃) δ; 3.29 (m, 2H), 5.92 (s, 2H), 6.43 (dt, J=2 Hzand 6 Hz, 1H), 6.74 (m, 1H), 6.86 (s, 1H) 6.95 (s, 1H)

(2) Synthesis of 5,6-Methylenedioxyindane-2-ol ##STR235##

A solution of 9.0 g of 5,6-methylenedioxyindene in 23 ml oftetrahydrofuran was cooled to 0° C. in a nitrogen atmosphere. A solutionof 2.2 ml of 10.0M borane/methyl sulfide complex in 5 ml oftetrahydrofuran was added dropwise thereto. The temperature of themixture was elevated from 0° C. to room temperature over 4 h and then1.8 ml of water was added dropwise thereto. 7.4 ml of a 3M aqueoussodium hydroxide solution and then 5.5 ml of a 35% aqueous hydrogenperoxide solution were added thereto under cooling with ice and themixture was stirred at room temperature overnight. The reaction mixturewas diluted with ethyl acetate, washed with an aqueous common saltsolution and dried over magnesium sulfate. The solvent was distilled offand the residue was crystallized from ethyl acetate to obtain 6.4 g ofthe intended compound in the form of white crystals.

m.p. (°C.); 99-100

¹ H-NMR (90 MHz, CDCl₃) δ; 1.73 (m, 1H), 2.79 (dd, J=4 Hz and 16 Hz,2H), 3.14 (dd, J=6 Hz and 16 Hz, 2H), 4.68 (m, 1H), 5.91 (s, 2H), 6.71(s, 2H)

(3) Synthesis of 2-Cyano-5,6-methylenedioxyindane ##STR236##

7.45 g of methanesulfonyl chloride was added dropwise to a solution of5.8 g of 5,6-methylenedioxyindane-2-ol and 9.1 ml of triethylamine in150 ml of dichloromethane under cooling with ice. The mixture wasstirred at 0° C. for 1 h. A mixture of ice and water was added to thereaction mixture and the resulting mixture was washed with a saturatedaqueous sodium hydrogencarbonate solution and dried over magnesiumsulfate. The solvent was distilled off to obtain 8.0 g of amethanesulfate, which was subjected to the subsequent reaction withoutpurification.

A mixture of 2.6 g of the methanesulfonate, 1.0 g of sodium cyanide anda solution of a catalytic amount of sodium iodide in 20 ml ofdimethylformamide was heated at 80° C. for 6 h. Water was added to thereaction mixture. After extraction with ether, the aqueous layer waswashed with water and an aqueous common salt solution and dried overmagnesium sulfate. The solvent was distilled off and the residue wasseparated according to silica gel column chromatography to obtain 0.4 gof the intended compound in the form of colorless crystals.

m.p. (°C.); 124-125

¹ H-NMR (90 MHz, CDCl₃) δ; 3.19 (m, 5H), 5.87 (s, 2H), 6.60 (s, 2H)

(4) Synthesis of (5,6-Methylenedioxyindane-2-yl)carboxylic Acid##STR237##

3.6 ml of a 35% aqueous hydrogen peroxide solution was added dropwise toa mixture of 1.4 g of 2-cyano-5,6-methylenedioxyindane, 50 ml of a 30%aqueous potassium hydroxide solution and 50 ml of ethanol. Then themixture was heated at 60° C. for 2 h and the solvent was distilled off.Dilute hydrochloric acid was added to the residue. After extraction withchloroform, the organic layer was dried over magnesium sulfate. Thesolvent was distilled off and the residue was recrystallized fromdiisopropyl ether to obtain 1.4 g of the intended compound in the formof colorless crystals.

m.p. (°C.); 168-169

¹ H-NMR (90 MHz, CDCl₃) δ; 3.00-3.44 (m, 5H), 5.85 (s, 2H), 6.60 (s,2H), 10.0 (bs, 1H)

EXAMPLE 12 Sodium (5,6-methylenedioxyindane-2-yl)carboxylate ##STR238##

1.5 g of the intended compound in the form of colorless crystals wasobtained from 1.4 g of (5,6-methylenedioxyindane-2-yl)carboxylic acid inthe same manner as that of Example 2.

m.p. (°C.); >270

¹ H-NMR (400 MHz, DMSO-d₆) δ; 2.77-3.04 (m, 5H), 5.89 (m, 2H), 6.68 (s,2H)

MS (FAB) m/z; 251 (MNa⁻), 229 (MH⁻)

EXAMPLE 13 (7,8-Dihydro-5H-1,3-dioxolo[4,5-g][2]benzopyran-5-yl)aceticAcid ##STR239## (1) Synthesis ofEthyl(7,8-dihydro-5H-1,3-dioxolo-[4,5-g][2]benzopyran-5-yl)acetate##STR240##

1.3 g of ethyl 3-{6-(2-hydroxyethyl)-1,3-benzodioxol-5-yl}acrylate wasdissolved in 30 ml of ethanol. A catalytic amount of sodium ethylate wasadded to the solution and the mixture was heated under reflux for 2 h.The solvent was distilled off and 1N hydrochloric acid and water wereadded to the residue. After extraction with ethyl acetate followed bywashing with a saturated aqueous common salt solution and drying overanhydrous magnesium sulfate, the solvent was distilled off. The residuewas purified according to silica gel column chromatography (hexane/ethylacetate=85:15) to obtain 0.78 g of the intended compound in the form ofa colorless oil.

¹ H-NMR (90 MHz, CDCl₃) δ; 1.27 (t, J=7.2 Hz, 3H), 2.35-3.1 (m, 4H),3.5-4.37 (m, 2H), 4.17 (q, J=7.2 Hz, 2H), 5.09 (dd, J=7.2 Hz and J=5.6Hz, 1H), 5.85 (s, 2H), 6.46 (s, 1H), 6.51 (s, 1H)

(2) Synthesis of(7,8-dihydro-5H-1,3-dioxolo[4,5-g][2]benzopyran-5-yl)acetic Acid##STR241##

0.78 g of ethyl(7,8-dihydro-5H-1,3-dioxolo[4,5-g][2]benzopyran-5-yl)acetate wasdissolved in 20 ml of ethanol. A solution of 0.35 g of sodium hydroxidein 4 ml of water was added thereto and the mixture was stirred underheating at 60° C. The solvent was distilled off and water was added tothe residue. The mixture was washed with ethyl acetate and acidifiedwith 1N hydrochloric acid. After extraction with chloroform, the extractwas washed with a saturated aqueous common salt solution and dried overanhydrous magnesium sulfate. After filtration, the solvent was distilledoff and the residue was subjected to silica gel column chromatography(chloroform) to obtain 0.67 g of the intended compound in the form ofcolorless crystals.

¹ H-NMR (90 MHz, CDCl₃) δ; 2.35-3.20 (m, 4H), 3.5-3.95 (m, 1H),3.92-4.28 (m, 1H), 4.95-5.25 (m, 1H), 5.87 (s, 2H), 6.46 (s, 1H), 6.52(s, 1H), 7.2-8.6 (br, 1H)

EXAMPLE 14 Sodium(7,8-dihydro-5H-1,3-dioxolo[4,5-g][2]benzopyran-5-yl)acetate ##STR242##

0.69 g of the intended compound in the form of colorless crystals wasobtained from 0.66 g of(7,8-dihydro-5H-1,3-dioxolo[4,5-g][2]benzopyran-5-yl)acetic acid in thesame manner as that of Example 2.

m.p. (°C.); 257.2-258 (dec.)

¹ H-NMR (90 MHz, DMSO-d₆) δ; 2.26 (d, J=6.5 Hz, 2H), 2.3-2.55 (m, 2H),3.35-4.05 (m, 2H), 4.89 (t, J=6.5 Hz, 1H), 5.83 (s, 1H), 6.52 (s, 1H),6.75 (s, 1H)

MS (FAB) m/z; 281 (MNa⁻), 259 (MH⁻)

COMPOUND GROUP (I-d) PREPARATIVE EXAMPLE 12-(1,3-Benzodioxol-5-yl)ethanethiol ##STR243##

750 g of 5-(2-bromoethyl)-1,3-benzodioxole was dissolved in 1 l ofethanol. 312 g of thiourea was added to the solution and the mixture washeated under reflux on a boiling water bath for 2 h. The reactionmixture was cooled and a solution of 300 g of sodium hydroxide in 1 l ofwater was added thereto. The resulting mixture was heated under refluxon a boiling water bath for 45 min. After cooling, 3 l of water wasadded thereto. After extraction with 5 l of ethyl acetate, the extractwas washed with dilute hydrochloric acid and then with water until thewashing became almost neutral. After drying over anhydrous sodiumsulfate followed by distillation of the solvent at 40° C., about 570 gof a faint yellow oil was obtained. This product was purified accordingto column chromatography (hexane/benzene=2:1) with about 3 kg of silicagel to obtain 310 g of the intended compound in the form of a colorlessoil.

¹ H-NMR (90 MHz, CDCl₃) δ; 1.36 (m, 1H), 2.6-2.9 (m, 4H), 5.87 (s, 2H),6.50-6.74 (m, 3H)

PREPARATIVE EXAMPLE 2 3-Acetoxy-4-(2-hydroxyethyl)-5-methylisoxazole##STR244##

7.8 g of 4-(2-hydroxyethyl)-5-methylisoxazol-3-ol was dissolved in 1 lof tetrahydrofuran. 1.70 g of sodium hydride was added to the solutionunder cooling with ice. The mixture was stirred at room temperature for30 min and then cooled again with ice. 4.7 g of acetyl chloride wasadded thereto and the mixture was stirred at room temperature. Thesolvent was distilled off and water was added to the residue. Afterextraction with chloroform, the extract was washed with a saturatedaqueous common salt solution and dried over anhydrous magnesium sulfate.After filtration, the solvent was distilled off and the residue waspurified according to silica gel column chromatography (chloroform) toobtain 2.96 g of the intended compound in the form of colorlessprismatic crystals.

¹ H-NMR (90MHz, CDCl₃) δ; 2.30 (s, 3H), 2.49 (t, J=6.1Hz, 2H), 2.56 (s,3H), 3.76 (t, J=6.1Hz, 2H).

PREPARATIVE EXAMPLE 3 5-(2-Hydroxyethyl)-2-methyl-1,3-benzodioxole##STR245##

A suspension of 1.0 g of 3,4-dihydroxyphenylacetic acid, 1.4 g of vinylacetate, 6 mg of mercury oxide (yellow) and 0.03 ml of boronfluoride/ethyl etherate in 9 ml of toluene was stirred at roomtemperature for 14 h. The reaction mixture was diluted with ethylacetate and washed with water and an aqueous common salt solution. Theorganic layer was dried over magnesium sulfate and the solvent wasdistilled off. An oil thus obtained was dissolved in 10 ml oftetrahydrofuran and the solution was added dropwise to a suspension of0.5 g of lithium aluminum hydride in tetrahydrofuran under cooling withice. The mixture was stirred at room temperature for 1 h. 0.5 ml ofwater, then 0.5 ml of a 15% aqueous sodium hydroxide solution andfinally 1.5 ml of water were added thereto and an insoluble matter wasfiltered off. The filtrate was concentrated and treated according tosilica gel column chromatography (ethyl acetate/hexane=1:1) to obtain0.8 g of the intended compound in the form of a colorless oil.

¹ H-NMR (90MHz, CDCl₃) δ; 1.66 (d, J=5Hz, 3H), 1.74 (m, 1H), 2.73 (t,J=6Hz, 2H), 3.72 (m, 2H), 6.14 (q, J=5Hz, 1H), 6.59 (s, 3H).

PREPARATIVE EXAMPLE 4 2,2-Dimethyl-5-(2-hydroxyethyl)-1,3-benzodioxole##STR246##

1.7 g of 3,4-dihydroxyphenylacetic acid, a catalytic amount ofp-toluenesulfonic acid, 10 ml of acetone and 10 ml of benzene wereheated under reflux for 18 h. The reflux solution was dehydrated withMolecular Sieve 4A. The reaction mixture was concentrated and theobtained dark brown oil was dissolved in 20 ml of tetrahydrofuran. Thesolution was added to a suspension of 0.8 g of lithium aluminum hydridein 30 ml of tetrahydrofuran under cooling with ice. The mixture wasstirred at room temperature for 1 h and then cooled with ice/water. 0.8ml of water, then 0.8 ml of a 15% aqueous sodium hydroxide solution andfinally 2.4 ml of water were added thereto and an insoluble substancewas filtered off. The filtrate was concentrated and treated according tosilica gel column chromatography (ethyl acetate/n-hexane=1:1) to obtain1.1 g of the intended compound in the form of a colorless oil.

¹ H-NMR (90MHz, CDCl₃) δ; 1.67 (s, 6H), 1.7 (m, 1H), 2.73 (t, J=6Hz,2H). 3.75 (bt, J=6Hz, 2H), 6.56 (m, 3H)

PREPARATIVE EXAMPLE 5 2-(6-Methyl-1,3-benzodioxol-5-yl)ethanol##STR247## (a) 5-(2-Benzyloxyethyl)-6-bromo-1,3-benzodioxole ##STR248##

15.0 g of 5-(2-acetoxyethyl)-1,3-benzodioxole was dissolved in 10 ml ofcarbon tetrachloride. 4.6 g of bromine was added to the solution undercooling with ice. The temperature was elevated to room temperature andthe reaction was conducted for 2 h. An aqueous sodium hydrogencarbonatesolution was added thereto. After extraction with chloroform, theextract was washed with an aqueous sodium sulfate solution and driedover magnesium sulfate. After concentration under reduced pressure, acrude bromine compound was obtained in the form of brown needles.

This product (non-purified) was added to a solution of 8.6 g of sodiumhydroxide in methanol and the reaction was conducted at 60° C. for 1.5h. Methanol was removed and water was added to the residue. Afterextraction with ethyl acetate, the extract was washed with water, driedover magnesium sulfate and concentrated under reduced pressure to obtaina yellow oily residue.

This residue (non-purified) was added to a solution of 3.8 g of sodiumhydride in 150 ml of dimethylformamide. The mixture was stirred at 60°C. for 30 min and the reaction mixture was cooled to room temperature.13.7 g of benzyl chloride was added dropwise thereto and the reactionwas conducted at 60° C. again for 1 h. The reaction mixture was pouredinto ice/water. After extraction with ethyl acetate, the extract wasdried over magnesium sulfate and concentrated under reduced pressure toobtain crude benzyl ether. After purification according to silica gelcolumn chromatography (ethylacetate/hexane=3:97), 12.0 g of the intendedcompound was obtained in the form of a faint yellow oil.

¹ H-NMR (90MHz, CDCl₃) δ; 2.98 (t, J=7Hz, 2H), 3.66 (t, J=7Hz, 2H), 4.54(s, 2H), 5.95 (s, 2H), 6.82 (s, 1H), 7.02 (s, 1H), 7.34 (s, 5H)

(b) 5-(2-Benzyloxyethyl)-6-methyl-1,3-benzodioxole ##STR249##

3.0 g of 5-(2-benzyloxyethyl)-6-bromo-1,3-benzodioxole was dissolved in100 ml of anhydrous ether. 8.5 ml of a 1.6 M solution of n-butyllithiumin hexane was added to the solution at -78° C. and the reaction wasconducted at -50° C. for 2 h. The reaction mixture was cooled again to-78° C. 6.4 g of methyl iodide was added thereto and the temperature wasgradually elevated to room temperature. Methanol and water were added tothe reaction mixture. After extraction with ethyl acetate, the extractwas dried over magnesium sulfate and concentrated under reduced pressureto obtain a crude methyl compound. After purification according tosilica gel column chromatography (ethylacetate/hexane=2:98), 1.9 g ofthe intended compound was obtained in the form of a pale yellow oil.

¹ H-NMR (90Hz, CDCl₃) δ; 2.20 (s,3H), 2.82 (t,J=7Hz,2H), 3.58 (t,J=7Hz,2H), 4.48 (s,2H), 5.82 (s, 2H), 6.56 (s,1H), 6.60 (s,1H), 7.44 (s,5H)

(c) 2-(6-Methyl-1,3-benzodioxol-5-yl)ethanol ##STR250##

1.9 g of 5-(2-benzyloxyethyl)-6-methyl-1,3-benzodioxole was dissolved in80 ml of ethanol. 0.2 g of 10% palladium/carbon (containing 50% water)and 4 ml of acetic acid was added thereto and the catalytic reductionwas conducted under 3 atm/cm² for 1 h. After removing palladium/carbon,ethanol was distilled off and the product was purified according tosilica gel column chromatography (ethyl acetate/hexane=2:3) to obtain1.0 g of the intended compound in the form of a faint yellow oil.

¹ H-NMR (90MHz, CDCl₃) δ; 1.88 (bs, 1H), 2.32 (s, 3H), 2.88 (t, J=7Hz,2H), 3.88 (t, J=7Hz, 2H), 5.96 (s, 2H), 6.76 (bs, 2H).

PREPARATIVE EXAMPLE 6 2-(6-Ethyl-1,3-benzodioxol-5-yl)ethanol ##STR251##(a) (6-Ethyl-1,3-benzodioxol-5-yl)acetic acid ##STR252##

Gaseous hydrogen chloride was introduced into a mixture of 500 ml ofconcentrated hydrochloric acid, 1 l of ethylacetate and 900 ml of anaqueous formaldehyde solution. A solution of 600 g of5-ethyl-1,3-benzodioxole in 300 ml of ethyl acetate was added dropwisethereto at 55° C. and the reaction was conducted for 1 h. Benzene wasadded thereto and the product was washed with water, dried overmagnesium sulfate and concentrated under reduced pressure to obtain acrude chlorine compound in the form of a faint yellow oil.

The crude chlorine compound was dissolved in 4 l of dimethyl sulfoxide.400 g of thoroughly triturated sodium cyanide was added to the solutionat room temperature and the mixture was stirred for 12 h. Water wasadded thereto. After extraction with ethyl acetate, the extract waswashed with water, dried over magnesium sulfate and concentrated underreduced pressure to obtain a crude cyano compound in the form of a brownoil.

A solution of the crude cyano compound prepared as above in 2 l ofethanol was added to a solution of 800 g of sodium hydroxide and themixture was heated under reflux for 16 h. Ethanol was distilled off fromthe reaction mixture was and water was added to the residue. Afterwashing with ether, the aqueous layer was acidified. After extractionwith chloroform, the extract was washed with water, dried over magnesiumsulfate and concentrated under reduced pressure.

The solid residue was recrystallized from ethyl acetate to obtain 400 gof the intended compound in the form of colorless crystals.

m.p.; 114°-115° C.

¹ H-NMR (90MHz, CDCl₃) δ; 1.16 (t, J=7Hz, 3H), 2.52 (q, J=7Hz, 2H), 3.54(s, 2H), 5.84 (s, 2H), 6.62 (s, 2H)

(b) 2-(6-Ethyl-1,3-benzodioxol-5-yl)ethanol ##STR253##

62 g of lithium aluminum hydride was suspended in 1.5 l of anhydroustetrahydrofuran. A solution of 200 g of(6-ethyl-1,3-benzodioxol-5-yl)acetic acid in 200 ml of tetrahydrofuranwas added dropwise to the suspension and the reaction was conducted atroom temperature for 12 h. After the completion of the reaction, waterwas added thereto and the precipitate was filtered off. The filtrate wasconcentrated under reduced pressure and water was added to the residue.After extraction with ethyl acetate, the extract was washed with water,dried over magnesium sulfate, concentrated under reduced pressure andpurified according to silica gel column chromatography (ethylacetate/hexane=1:4) to obtain 169 g of the intended compound in the formof a faint yellow oil.

¹ H-NMR (90MHz, CDCl₃) δ; 1.16 (t, J=7Hz, 3H), 2.80 (bs, 1H), 2.54 (q,J=7Hz, 2H), 2.78 (t, J=7Hz, 2H), 3.74 (t, J=7Hz, 2H), 5.84 (s, 2H), 8.60(s, 1H), 6.62 (s, 1H)

PREPARATION EXAMPLE 7 2-(6-Propyl-1,3-benzodioxol-5-yl)ethanol##STR254## (a) (6-Propyl-1,3-benzodioxol-5-yl)acetonitrile ##STR255##

15 g of piperonyl butoxide and 300 ml of concentrated hydrochloric acidwere dissolved in 100 ml of benzene and the solution was heated underreflux for 3 h. The reaction mixture was cooled to room temperature andwater was added thereto. After extraction with ethyl acetate, theextract was washed with water, dried over magnesium sulfate andconcentrated under reduced pressure to obtain 12 g of6-propyl-5-chloromethyl-1,3-benzodioxole in the form of a faint brownoil.

2.0 g of the product was dissolved in 30 ml of dimethyl sulfoxide. 1.5 gof thoroughly triturated sodium cyanide was added to the solution andthe reaction was conducted at room temperature for 2 h. The reactionmixture was poured into water. After extraction with ethyl acetate, theextract was washed with water, dried over magnesium sulfate,concentrated under reduced pressure and purified according to silica gelcolumn chromatography (ethyl acetate/hexane=7:93) to obtain 1.7 g of theintended compound in the form of colorless needles.

m.p.; 66° C.-67° C.

¹ H-NMR (90 MHz, CDCl₃) δ; 0.98 (t, J=7Hz, 3H), 1.60 (sext, J=7Hz, 2H),2.52 (t, J=7Hz, 2H), 3.64 (s, 2H), 5.96 (s, 2H), 6.72 (s, 1H), 6.84 (s,1H)

(b) 2-(6-Propyl-1,3-benzodioxol-5-yl)ethanol ##STR256##

1.7 g of (6-propyl-1,3-benzodioxol-5-yl)acetonitrile was added to asolution of 1.7 g of potassium hydroxide in 40 ml of 50% hydrousethanol. The mixture was heated under reflux for 14 h. Ethanol wasdistilled off from the reaction mixture under reduced pressure and waterwas added to the residue. After washing with ether, the aqueous layerwas acidified. After extraction with chloroform, the extract was washedwith water, dried over magnesium sulfate and concentrated under reducedpressure to obtain 2-(6-propyl-1,3-benzodioxol-5-yl)acetic acid.

This product was added to a solution of 0.64 g of lithium aluminumhydride in 20 ml of tetrahydrofuran at 0° C. and the reaction wasconducted for 1 h. Water was added to the reaction mixture and aprecipitate thus formed was filtered off. The filtrate was concentratedand purified according to silica gel column chromatography (ethylacetate/hexane=3:7) to obtain 1.4 g of the intended compound in the formof a colorless oil.

¹ H-NMR (90MHz, CDCl₃) δ; 0.96 (t, J=7Hz, 3H), 1.56 (sext, J=7Hz, 2H),2.52 (t, J=7Hz, 2H), 2.80 (t, J=7Hz, 2H), 3.78 (t, J=7Hz, 2H), 5.89 (s,2H), 6.68 (s, 2H)

PREPARATIVE EXAMPLE 8 1-(1,3-Benzodioxol-5-yl)-2-methyl-1-propene##STR257##

62.5 ml of a 1.6 M solution of butyllithium in hexane was added to 500ml of anhydrous ether. 38.5 g of isopropyltriphenylphosphonium bromidewas added thereto in a nitrogen gas stream and the mixture was stirredfor 4 h. 18 g of piperonal was added to the reaction mixture and theresulting mixture was stirred for 5.5 h and then filtered. The filtratewas washed with 1 l of ether, concentrated under reduced pressure andpurified according to silica gel column chromatography (hexane/ethylacetate=10:1) to obtain 13.1 g of the intended compound in the form of acolorless oil.

¹ H-NMR (90MHz, CDCl₃) δ; 1.83 (d, J=1Hz, 3H), 1.86 (d, J=1Hz, 3H), 5.92(s, 2H), 6.15 (m, 1H), 6.56-6.82 (m, 3H)

PREPARATION EXAMPLE 92-[{2-(1,3-Benzodioxol-5-yl)ethyl)thio]ethanesulfonyl chloride##STR258## (a) Sodium2-[{2-(1,3-benzodioxol-5-yl)ethyl}thio]-ethanesulfonate ##STR259##

15 g of 2-(1,3-benzodioxol-5-yl)ethanoethiol and 17.4 g of sodium2-bromoethanesulfonate were dissolved in a mixture of 280 ml of ethanoland 120 ml of water. 3.3 g of sodium hydroxide was added to the solutionand the mixture was heated under reflux for 1 h. The reaction mixturewas concentrated and 500 ml of ethyl acetate and 500 ml of water wereadded thereto. After separation of the layers, the aqueous layer wasacidified with hydrochloric acid. After extraction with n-butanol, theextract was washed with a saturated aqueous common salt solution. Thesolvent was distilled off to obtain 19 g of a faint yellow residue. Thisproduct was dissolved in a solution of 2.94 g of sodium hydroxide indilute methanol and recrystallized therefrom to obtain 14.7 g of theintended compound in the form of colorless crystals.

¹ H-NMR (90MHz, DMSO-d₆) δ; 2.72 (s, 8H), 5.94 (s, 2H), 6.56-6.88 (m,3H)

(b) 2-[{2-(1,3-Benzodioxol-5-yl)ethyl}thio]ethanesulfonyl chloride##STR260##

1.9 g of sodium 2-[{2-(1,3-benzodioxol-5-yl)-2-ethylthiolethanesulfonatewas suspended in 4 m of N,N-dimethylformamide. 0.89 of thionyl chloridewas added dropwise to the suspension under cooling with ice/water. Themixture was stirred under cooling with water for 20 min. After addingice/water and then a mixture of 200 ml of chloroform and 200 ml of waterto the reaction mixture, the layers thus formed were separated. Thechloroform layer was washed with water and dried over anhydrous sodiumsulfate. The solvent was distilled off to obtain 2.1 g of the intendedcompound in the form of a colorless oil.

¹ H-NMR (90MHz, CDCl₃) δ; 2.83 (s,4H), 2.92-3.15 (m, 2H), 3.65-3.94 (m,2H), 5.94 (s, 2H), 6.56-6.85 (m, 3H)

EXAMPLE 1 [{2-(1,3-Benzodioxol-5-yl)ethyl)thio]propan-2-one ##STR261##

10 g of 2-(1,3-benzodioxol-5-yl)ethanoethiol and 5.1 g of1-chloro-2-propanone were dissolved in 200 ml of 90% ethanol, 2.2 g ofsodium hydroxide was added to the solution and the mixture was heatedunder reflux for 10 min to conduct the reaction. The reaction mixturewas concentrated under reduced pressure. 200 ml of ethyl acetate wasadded thereto to obtain a solution, which was washed with water threetimes. After drying over anhydrous sodium sulfate, the solvent wasdistilled off and the residue was purified according to silica gelcolumn chromatography (benzene/ethyl acetate=30:1) to obtain 11.1 g ofthe intended compound in the form of a colorless oil.

¹ H-NMR (90MHz, CDCl₃) δ; 2.25 (s, 3H), 2.50-2.90 (m, 4H), 3.17 (s, 2H),5.85 (s, 2H), 6.40-6.75 (m, 3H)

MS m/z; 238 (M⁻), 149

EXAMPLE 2 [{2-(1,3-Benzodioxol-5-yl)ethyl}thiol]acetonitrile ##STR262##

8.5 g of the intended compound in the form of a colorless oil wasobtained from 4.2 g of 2-(1,3-benzodioxol-5-yl)ethanethiol and 4.2 g ofchloroacetonitrile in the same manner as that of Example 1.

¹ H-NMR (90MHz, CDCl₃) δ; 2.76-3.03 (m, 4H), 3.22 (s, 2H), 5.91 (s, 2H),6.56-6.82 (m, 3H)

MS m/z; 221 (M⁻) 135

EXAMPLE 3 2-Methyl-2-[{2-(1,3-benzodioxol-5-yl)ethyl}thio]propionic acid##STR263##

6 g of the intended compound in the form of a colorless oil was obtainedfrom 6 g of 2-(1,3-benzodioxol-5-yl)ethanethiol and 4.6 g of2-bromo-2-methylpropionic acid in the same manner as that of Example 1.

¹ H-NMR (90MHz, CDCl₃) δ; 1.53 (s, 6H), 2.70-2.90 (m, 4H), 5.90 (s, 2H),6.52-6.80 (m, 3H)

EXAMPLE 4 Sodium2-methyl-2-[{2-(1,3-benzodioxol-5-yl)ethyl}thio]propionate ##STR264##

A solution of 0.90 g of sodium hydroxide in 9.0 ml of water was added to6 g of 2-methyl-2-[{2-(1,3-benzodioxol-5-yl)ethyl}thio]propionic acid toobtain a solution. 100 ml of ethanol was added to the solution and thesolvent was distilled off. The residue was washed with ether. Afterfiltration, the product was dried under reduced pressure to obtain 6 gof the intended compound in the form of a white powder.

mp.; 261°-265° C.

¹ H-NMR (90MHz, DMSO-d₆) δ; 1.32 (s, 6H), 2.52-2.82 (m, 4H), 5.90 (s,2H), 6.48-6.80 (m, 3H)

MS (FAB) m/z; 313 (MNa⁻), 291 (MH⁺)

EXAMPLE 5 2-Oxo-3-[{2-(1,3-benzodioxol-5-yl)ethyl}thiol]propionic acid##STR265##

0.21 g of the intended compound was obtained as a keto-enol tautomericmixture of 2:1 in the form of faint yellow crystals from 0.50 g of2-(1,3-benzodioxol-5-yl)ethanethiol and 0.43 g of 3-bromopyruvic acid inthe same manner as that of Example 1.

mp.; 131°-132° C.

¹ H-NMR (90MHz, CDCl₃ -DMSO-d₆) δ; 2.40-3.08 (m, 2H+1H÷1/3), 5.87 (s,2H), 6.20 (s, 1H×2/3), 6.40-6.84 (m, 3H), 8.10 (bs, 1H)

MS m/z; 268 (M⁻)

EXAMPLE 6 2-(1,3-Benzodioxol-5-yl)ethyl (pyridin-4-yl)methyl sulfide##STR266##

3.30 g of 2-(1,3-benzodioxol-5-yl)ethanethiol was dissolved in 30 ml ofethanol. 1.65 g of sodium hydroxide and then 2.70 g of 4-picolylchloride hydrochloride were added to the solution and the mixture washeated under reflux at 70° C. for 30 min. The solvent was distilled offand water was added to the residue. After extraction with ethyl acetate,1N hydrochloric acid was added to the extract. The aqueous layer wasacidified, taken up and washed with ethylacetate. The pH of the aqueouslayer was adjusted to 8 with potassium carbonate. After extraction withethyl acetate, the extract was washed with a saturated aqueous commonsalt solution and dried over anhydrous magnesium sulfate. Afterfiltration, the solvent was distilled off and the residue was purifiedaccording to silica gel column chromatography (ethyl acetate/hexane=1:4)to obtain 2.69 g of the intended compound in the form of a colorlessoil.

¹ H-NMR (90MHz, CDCl₃) δ; 2.4-2.87 (m, 4H), 3.60 (s, 2H), 5.86 (s, 2H),6.35-6.75 (m, 3H), 7.05-7.25 (m, 2H), 8.25-8.57 (m, 2H)

MS (FO) m/z; 273 (M⁻)

EXAMPLE 7 2-(1,3-Benzodioxol-5-yl)ethyl (pyridin-2-yl)methyl sulfide##STR267##

2.3 g of the intended compound in the form of a colorless oil wasobtained from 3.0 g of 2-(1,3-benzodioxol-5-yl)ethanethiol and 2.7 g of2-picolyl chloride hydrochloride in the same manner as that of Example6.

¹ H-NMR (90MHz, CDCl₃) δ; 2.55-2.9 (m, 4H), 3.86 (s, 2H), 5.91 (s, 2H),6.45-6.8 (m, 3H), 7.0-7.3 (m, 1H), 7.33 (bd, J=7.9Hz, 1H), 7.61 (td,J=7.9 and 2.2Hz, 1H), 8.51 (bd, J=5.8 Hz, 1H)

MS (FO) m/z; 273 (M⁻)

EXAMPLE 8 2-(1,3-Benzodioxol-5-yl)ethyl (imidazol-4-yl)methyl sulfide##STR268##

40 ml of thionyl chloride was added to 2.50 g of 4-hydroxyethylimidazolehydrochloride. The mixture was stirred under heating at 70° C. for 1 h.Thionyl chloride was distilled off. 3.39 g of2-(1,3-benzodioxol-5-yl)ethanethiol, 40 ml of ethanol and 1.50 g ofsodium hydroxide were added to the residue and the mixture was stirredunder heating at 70° to 80° C. for 1 h. The solvent was distilled offand water was added to the residue. After extraction with chloroformcontaining 5% of methanol, the extract was dried over anhydrousmagnesium sulfate, dried and filtered. The solvent was distilled off andthe residue was purified according to silica gel column chromatography(methanol/choroform=1:49) to obtain 1.94 g of the intended compound inthe form of colorless prismatic crystals.

mp.; 81°-83° C.

¹ H-NMR (90MHz, CDCl₃) δ; 2.45°-2.9(m, 4H), 3.68 (s, 2H), 5.84 (s, 2H),5.8-6.9 (broad, 1H), 6.4-6.75 (m, 3H), 6.86 (bs, 1H), 7.53 (bs, 1H)

MS m/z; 262 (M⁻)

EXAMPLE 94-[2-{2-(1,3-Benzodioxol-5-yl)ethyl)thio]ethyl-5-methylisoxazol-3-ol##STR269##

100 ml of tetrahydrofuran and 4.66 g of triethylamine were added to 2.84g of 3-acetoxy-4-[ 2-hydroxyethyl)-5-methylisoxazole. 4.39 g ofmethanesulfonyl chloride was added dropwise thereto at -15° C. and themixture was stirred at 0° C. or below for 1 h. The solvent was distilledoff. After addition of ice/water followed by extraction with chloroform,the extract was washed with 1N hydrochloric acid, water, a saturatedaqueous sodium hydrogencarbonate solution and a saturated aqueous commonsalt solution in this order and then dried over anhydrous magnesiumsulfate. The solvent was distilled off and the resultingmethanesulfonate was added to a solution comprising 4.19 g of2-(1,3-benzodioxol-5-yl)ethanethiol, 30 ml of ethnaol and 1.53 g ofsodium hydroxide and the mixture was stirred under heating at 70° C. Thesolvent was distilled off and water was added to the residue. Afterextraction with chloroform containing 5% of methanol, the extract waswashed with a saturated aqueous common salt solution and dried overanhydrous magnesium sulfate. After filtration, the filtrate wasconcentrated, purified according to silica gel column chromatography andrecrystallized from ethyl acetate/hexane to obtain 0.96 g of theintended compound in the form of colorless needles.

mp.; 81°-81.5° C.

¹ H-NMR (90MHz, CDCl₃) δ; 2.25 (s, 3H), 2.35-2.85 (m, 8H), 5.87 (s, 2H),5.4-6.5 (br, 1H), 6.45-6.75 (m, 3H)

MS m/z; 307 (M⁺)

EXAMPLE 10 Sodium4-[2-{2-(1,3-benzodioxol-5-yl)ethyl}thio]-ethyl-5-methylisoxazol-3-ol##STR270##

1.01 g of the intended compound in the form of a white powder wasobtained from 0.95 g of4-[2-{2-(1,3-benzodioxol-5-yl)ethyl}thiol]ethyl-5-methylisoxazol-3-ol inthe same manner as that of Example 4.

mp.; 144°-152° C. (dec.)

¹ H-NMR (90MHz, DMSO-d₆) δ; 1.98 (s, 3), 2.1-2.8 (m, 4H), 2.68 (bs, 4H),5.33 (s, 2H), 6.48-6.9 (m, 8H)

MS (FAB) m/z 352 (MNa⁻), 330 (MH⁻)

EXAMPLE 11 [(2-(2-Methyl-1,3-benzodioxol-5-yl)ethyl)thio]-acetic acid##STR271##

0.97 g of methanesulfonyl chloride was added dropwise to a solution of0.76 g of 5-(2-hydroxyethyl)-2-methyl-1,3-benzodioxole and 1.2 ml oftriethylamine in 10 ml of methylene chloride and the mixture was stirredat room temperature for 30 min. The reaction mixture was diluted withchloroform, washed with cold water, then a saturated sodiumhydrogencarbonate solution and finally an aqueous common salt solutionand dried over magnesium sulfate. The solvent has distilled off. 0.9 gof mercaptoacetic acid, 10 ml of a 10% sodium hydroxide solution and 10ml of ethanol were added to the oil (mesylate) thus obtained and themixture was heated at 80° C. for 30 min. The reaction mixture wasconcentrated and the aqueous layer was washed with ethyl ether and thenacidified with dilute hydrochloric acid. The aqueous layer was extractedwith chloroform and dried over magnesium sulfate. The solvent wasdistilled off and the product was purified according to silica gelcolumn chromatography (methanol/chloroform= 1:99) to obtain 1.0 g of theintended compound in the form of a faint brown oil.

¹ H-NMR (90MHz, CDCl₃) δ; 1.66 (d, J=5Hz, 3H), 2.84 (s, 4H), 3.24 (s,2H), 6.20 (q, J=5Hz, 1H), 6.63 (m, 3H), 9.95 (m, 1H)

EXAMPLE 12 Sodium [{2-(2-methyl-1,3-benzodioxol-5-yl)ethyl}thio]acetate##STR272##

0.7 g of the intended compound in the form of a white powder wasobtained from 1.0 g of[{2-(2-methyl-1,3-benzodioxol-5-yl)ethyl)thio]acetic acid in the samemanner as that of Example 4.

mp.; 200°-205° C. (dec.)

¹ H-NMR (400MHz, DMSO-d₆) δ; 1.58 (d, J=4.8Hz, 3H), 2.68 (m, 4H), 2.96(s, 2H), 6.28 (q, J=4.8Hz, 1H), 6.62-6.75 (m, 3H)

MS (FAB) m/z 299 (MNa⁻), 276 (MH⁻)

EXAMPLE 13 [{2-(2,2-Dimethyl-1,3-benzodioxol-5-yl)ethyl}-thio]acetateacid ##STR273##

3.4 g of the intended compound in the form of a colorless oil wasobtained from 4.3 g of 2,2-dimethyl-5-(2-hydroxyethyl)-1,3-benzodioxolein the same manner as that of Example 11.

¹ H-NMR (90MHz, CDCl₃) δ; 1.65 (s, 6H), 2.84 (s, 4H), 3.25 (s, 2H), 6.61(m, 3H), 9.84 (m, 1H)

EXAMPLE 14 Sodium[{2-(2,2-dimethyl-1,3-benzodioxol-5-yl)ethyl}-thio]acetate ##STR274##

3.3 g of the intended compound in the form of a white powder wasobtained from 3.3 g of[{2-(2,2-dimethyl-1,3-benzodioxol-5-yl)ethyl}thio]acetic acid in thesame manner as that of Example 4.

mp.; 199°-202° C. (dec.)

¹ H-NMR (400MHz, DMSO-d₆) δ; 1.60 (s, 6H), 2.68 (s, 4H), 2.95 (s, 2H),6.60-6.71 (m, 3H)

MS (FAB) m/z 313 (MNa⁻), 291 (MH⁻)

EXAMPLE 15 [{2-(6-Methyl-1,3-benzodioxol-5-yl)ethyl}thio]acetic acid##STR275##

1.5 g of the intended compound in the form of a white powder wasobtained from 1.5 g of 2-(6-methyl-1,3-benzodioxol-5-yl)ethanol in thesame manner as that of Example 11.

¹ H-NMR (90MHz, CDCl₃) δ; 2.22 (s, 3H), 2.82 (s, 4H), 3.26 (s, 2H), 5.88(s, 2H), 6.66 (s, 2H), 10.56 (bs, 1H)

EXAMPLE 16 Sodium [{2-(6-methyl-1,3-benzodioxol-5-yl)ethyl}-thio]acetate##STR276##

1.6 g of the intended compound in the form of a white powder wasobtained from 1.5 g of[{2-(6-methyl-1,3-benzodioxol-5-yl)ethyl)thio]acetic acid in the samemanner as that of Example 4.

mp.; 194°-195° C.

¹ H-NMR (400MHz, DMSO-d₆) δ; 2.17 (s, 3H), 2.59-2.63 (m, 2H), 2.67-2.72(m, 2H), 2.96 (s, 2H), 5.90 (s, 2H), 6.70 (s, 1H), 6.75 (s, 1H)

MS (FAB) m/z; 277 (MH⁻)

EXAMPLE 17 [{2-(6-Ethyl-1,3-benzodioxol-5-yl)ethyl}thio]acetic acid##STR277##

85 g of the intended compound in the form of a white powder was obtainedfrom 169 g of 2-(6-ethyl-1,8-benzodioxol-5-yl)ethanol in the same manneras that of Example 11.

mp.; 63°-64° C.

¹ H-NMR (90 MHz, CDCl₃) δ; 1.16 (t, J=7Hz, 3H), 2.52 (q, J=7Hz, 2H),2.82 (s, 4H), 3.24 (s, 2H), 5.84 (s, 2H), 6.58 (s, 1H), 6.60 (s, 1H),9.80 (bs, 1H)

EXAMPLE 18 Sodium [{2-(6-ethyl-1,3-benzodioxol-5-yl)ethyl}thio]-acetate##STR278##

91 g of the intended compound in the form of a white powder was obtainedfrom 85 g of [{2-(6-ethyl-1,3-benzodioxol-5-yl)ethyl}thio]acetic acid inthe same manner as that of Example 4.

mp.; 193°-196° C. (dec.)

¹ H-NMR(400MHz, DMSO-d₆) δ; 1.10 (t, J=7Hz, 3H), 2.51 (q, J=7Hz, 2H),2.60-2.65 (m, 2H), 2.69-2.74 (m, 2H), 2.79 (s, 2H), 5.91 (s, 2H), 6.71(s, 1H), 6.75 (s, 1H)

MS (FAB) m/z; 2.91 (MH⁻)

EXAMPLE 19 [{2-(6-Propyl-1,3-benzodioxol-5-yl)ethyl}thio]acetic acid##STR279##

1.4 g of the intended compound in the form of colorless crystals wasobtained from 1.4 g of 2-(6-propyl-1,3-benzodioxol-5-yl)ethanol in thesame manner as that of Example 11.

mp.; 72.5°-73.5° C.

¹ H-NMR (90MHz, CDCl₃) δ; 0.96 (t, J=7Hz, 3H), 1.56 (sext, J=7Hz, 2H),2.52 (t, J=7Hz, 2H), 2.84 (s, 4H), 3.48 (s, 2H), 5.90 (s, 2H), 6.64 (s,2H)

EXAMPLE 20 Sodium [{2-(6-propyl-1,3-benzodioxol-5-yl)ethyl}-thio]acetate##STR280##

1.5 g of the intended compound in the form of a white powder wasobtained from 1.4 g of[(2-(6-propyl-1,3-benzodioxol-5-yl)ethyl}thio]acetic acid in the samemanner as that of Example 4.

mp.; 189°-190° C.

¹ H-NMR (400MHz, DMSO-d₆) δ; 0.96 (t, J=7 Hz, 3H), 1.49 (sext, J=7Hz,2H), 2.46 (t, J=8Hz, 2H), 2.62-2.64 (m, 2H), 2.69-2.72 (m, 2H), 3.00 (s,2H), 5.90 (s, 2), 6.69 (s, 1H), 6.75 (s, 1H)

MS (FAB) m/z; 305 (MH⁻)

EXAMPLE 21 3-{6-(2-Ethylthio)ethyl-1,3-benzodioxol-5-yl)propionic acid##STR281##

2.2 g of the intended compound in the form of a white powder wasobtained from 3.5 g of ethyl3-{6-(2-methanesulfonyloxy)ethyl-1,3-benzodioxol-5-yl}propionate and 1 gof ethyl mercaptan in the same manner as that of Example 11.

¹ H-NMR (90MHz, CDCl₃)δ; 1.28 (t, J=7.2Hz, 3H), 2.50-9.10 (m, 10H), 5.99(s, 2H), 6.75 (s, 2H)

EXAMPLE 22 Sodium3-{6-(2-ethylthio)ethyl-1,3-benzodioxol-5-yl}propionate ##STR282##

1.9 g of the intended compound in the form of a white powder wasobtained from 2.2 g of3-{6-(2-ethylthio)ethyl-1,3-benzodioxol-5-yl}propionic acid in the samemanner as that of Example 4.

mp.; 218°-222° C.

¹ H-NMR (90MHz, DMSO-d₆) δ; 1.20 (t, J=7.2 Hz, 3H), 1.94-2.26 (m, 2H),2.28-2.88 (m, 8H), 5.84 (s, 2H), 6.67 (s, 2H)

MS (FAB) m/z; 327 (MNa⁻), 305 (MH⁻)

EXAMPLE 23 [[{(2-(1,3-Benzodioxol-5-yl)-1,1-dimethyl}ethyl]thio]aceticacid ##STR283##

30 ml of benzene was added to a mixture of 5 g of1-(1,3-benzodioxol-5-yl)-2-methyl-1-propene, 2.6 g of mercaptoaceticacid and a catalytic amount of α,α'-azobisisobutyronitrile. The mixturewas refluxed for 2 days. 2.6 g of mercaptoacetic acid was added theretoand the mixture was refluxed for one week. 200 ml of ethyl acetate and200 ml of water were added to the reaction mixture and the layers thusformed were separated. An aqueous sodium carbonate solution was added tothe ethyl acetate layer to extract the intended compound. The aqueouslayer was acidified with dilute hydrochloric acid. After extraction withethyl acetate, the extract was washed with water and dried overanhydrous sodium sulfate. The solvent was distilled off and the residuewas purified according to silica gel column chromatography (hexane/ethylacetate/acetic acid=20:80:1). The product was dissolved in ethylacetate, washed with water to remove acetic acid and dried overanhydrous sodium sulfate. The solvent was distilled off to obtain 3.33 gof the intended compound in the form of a colorless oil.

¹ H-NMR (90MHz, CDCl₃) δ; 1.29 (s, 6H) 2.78 (s, 2H), 3.29 (s, 2H), 5.92(s, 2), 6.52-6.80 (m, 3H)

EXAMPLE 24 Sodium[[{2-(1,3-benzodioxol-5-yl)-1,1-dimethyl}-ethyl]thio]acetate ##STR284##

2.1 g of the intended compound in the form of colorless crystals wasobtained from 3.33 g of[[{2-(1,3-benzodioxol-5-yl)-1,1-dimethyl}ethyl]thio]acetic acid in thesame manner as that of Example 4.

mp.; 206°-210° C.

¹ H-NMR (90MHz, DMSO-d₆) δ; 1.14 (s, 6H), 2.68 (s, 2H), 3.02 (s, 2H),5.94 (s, 2H), 6.52-6.88 (m, 3H)

MS (FD) m/z; 313 (MNa⁻), 291 (MH⁻)

EXAMPLE 25 [[1-{(1,3-Benzodioxol-5-yl)methyl}propyl]thio]acetic acid##STR285##

2.2 g of 5-(1-butenyl)-1,3-benzodioxole and 5.4 g of mercaptoacetic acidwere heated at 60° C. for 3 h. The reaction mixture was diluted withethyl acetate, washed with water and an aqueous common salt solution anddried over magnesium sulfate. The solvent was distilled off and theproduct was separated according to silica gel column chromatography(chloroform) to obtain 1.8 g of the intended compound in the form of acolorless oil.

¹ H-NMR (90MHz, CDCl₃) δ; 1.00 (t, J=7Hz, 3H), 1.54 (m, 2H), 2.69-3.00(m, 3H), 3,14 (s, 2), 5.87 (s, 2H), 6.62 (m, 3H), 8.7 (m, 1H)

EXAMPLE 26 Sodium [[1-{(1,3-benzodioxol-5-yl)methyl}propyl]thio]acetate##STR286##

1.7 g of the intended compound in the form of a white powder wasobtained from 1.7 g of[[1-{(1,3-benzodioxol-5-yl)methyl}propyl]thio]acetic acid in the samemanner as that of Example 4.

mp.; 184°-188° C. (dec);

¹ H-NMR (400MHz, DMSO-d₆) δ; 0.89 (t, d= 7.3Hz, 3H), 1.31 (m, 1H), 1.48(m, 1H), 2.43-2.59 (m, 1H), 2.80-2.90 (m, 2H), 2.90 and 2.96 (ABq,J=13.2Hz, 2H), 5.96 (m, 2H), 6.65 (m, 1H), 6.77-6.82 (m, 2H)

MS (FAB) m/z; 291 (MH⁻)

EXAMPLE 27 [{2-(1,3-Benzodioxol-5-yl)ethyl}thio]cyanoacetic acid##STR287##

5.0 g of [{2-(1,3-benzodioxol-5-yl)ethyl)thio]acetonitrile was dissolvedin 50 ml of anhydrous ether. 22 ml of a 1.6 M solution of n-butyllithiumin hexane was added to the solution at -78° C. The mixture was stirredat -50° C. for 2 h. It was cooled again to -78° C. and 10 g of dry icewas added thereto. The temperature of the mixture was elevated to roomtemperature. Water was added to the reaction mixture. After extractionwith chloroform, the extract was dried over magnesium sulfate andconcentrated. The residue was purified according to silica gel columnchromatography (chloroform) and recrystallized from ethyl acetate/hexaneto obtain 0.70 g of the intended compound of the form of colorlessneedles.

mp.; 106°-107° C.

¹ H-NMR (90MHz, DMSO-d₆) δ; 2.62-3.10 (m, 4H), 5.12 (s, 1H), 5.90 (s,2H), 6.50-6.86 (m, 3H)

MS (FAD) m/z; 265 (MH⁻¹)

EXAMPLE 28 Sodium [{2-(1,3-benzodioxol-5-yl)ethyl}thio]cyanoacetate##STR288##

0.59 g of the intended compound in the form of a white powder wasobtained from 0.70 g of [{2-(1,3-benzodioxol-5-yl)ethyl}thio]cyanoaceticacid in the same manner as that of Example 4.

mp.; 202°-208° C. (dec.)

¹ H-NMR (400MHz, DMSO-d₆) δ; 2.80-2.84 (m,2H), 2.88-2.92 (m, 2H),4.25-4.50 (bs, 1H), 5.97 (s, 2H), 6.70-6.88 (m, 3H)

MS (FAB) m/z; 310 (MNa⁻)

EXAMPLE 29N,N-Dimethyl-2-[{2-(1,3-benzodioxol-5-yl)-2-ethyl}thio]ethanesulfonamide##STR289##

4 g of 2-[{2-(1,3-benzodioxol-5-yl)ethyl}thio]ethanesulfonyl chloridewas dissolved in chloroform. Gaseous dimethylamine was introducedthereinto under stirring. The chloroform solution was washed with waterand dried over anhydrous sodium sulfate. The solvent was distilled offand the residue was purified according to silica gel columnchromatography (chloroform). The product was recrystallized fromisopropyl ether/ethanol to obtain 3.0 g of the intended compound in theform of colorless crystals.

mp.; 93°-94.5° C.

¹ H-NMR (90MHz, CDCl₃) δ; 2.75 (s, 4H), 2.83 (s, 6H), 2.63-3.19 (m, 4H),5.86 (s, 2H), 6.43-6.76 (m, 3H),

MS m/z; 317 (M⁻), 149, 135

EXAMPLE 30 [{2-(1,3-Benzodioxol-5-yl)ethyl}sulfinyl]propan-2-one##STR290##

4 g of [{2-(1,3-benzodioxol-5-yl)ethyl}thio]propan-2-one was dissolvedin 70 ml of chloroform. 3.2 g of 90% m-chloroperbenzoic acid was addedto the solution under cooling with ice/water. The mixture was stirredfor 40 min. 150 ml of chloroform and an aqueous sodium carbonatesolution were added to the reaction mixture. After separation of thelayers thus formed, the chloroform layer was washed with water threetimes and dried over anhydrous sodium sulfate. The solvent was distilledoff and the residue was recrystallized from isopropyl ether to obtain3.5 g of the intended compound in the form of colorless crystals.

mp.; 82°-84.5° C.

¹ H-NMR (90MHz, CDCl₃) δ; 2.32 (s, 3H), 2.99 (s, 4H), 3.65 and 3.77(ABq, J=13.5Hz, 2H), 5.89 (s, 2H), 6.50-6.77 (m, 3H)

MS (FAB) m/z; 255 (MH⁻), 149

EXAMPLE 31 5-{2-(Ethylsulfinyl)ethyl}-13-benzodioxole ##STR291##

3.0 g of the intended compound in the form of colorless crystals wasobtained from 4 g of 5-(2-ethylthio)ethyl-1,3-benzodioxole in the samemanner as that of Example 30.

mp.; 60.5°-61.5° C.

¹ H-NMR (90MHz, CDCl₃) δ; 1.33 (t,J=7.2Hz, 3H), 2.71 (q, J=7.2Hz, 2H),2.72-3.18 (m, 4H), 5.92 (s, 2), 6.54-6.83 (m, 3H)

MS (FAB) m/z; 227 (MH⁻)

EXAMPLE 32 5-{2-(1-Methylethylsulfinyl)ethyl}-1,3-benzodioxole##STR292##

3.7 g of the intended compound in the form of colorless oil was obtainedfrom 4 of 5-{2-(1-methylethyl)thio}ethyl-1,3-benzodioxole in the samemanner as that of Example 30.

¹ H-NMR (90MHz, CDCl₃) δ; 1.24 (d, J=5.4Hz, 3), 1.31 (d, J=5.4Hz,3H),2.45-3.27 (m, 5H), 5.88 (s, 2H), 6.53-6.78 (m, 3H)

MS (FAB) m/z; 241 (MH⁻), 149

EXAMPLE 33 [{2-(1,3-Benzodioxol-5-yl)ethyl)sulfinyl]acetonitrile##STR293##

3.0 g of the intended compound in the form of colorless crystals wasobtained from 3 g of [{2-(1,3-benzodioxol-5-yl)ethyl}thio]acetonitrilein the same manner as that of Example 30.

mp.; 57°-59.5° C.

¹ H-NMR (90MHz, CDCl₃) δ; 2.76-3.34 (m, 4H), 3.53 and 3.69 (ABq, J=16.4Hz, 2H), 5.90 (s, 2H), 6.52-6.79 (m, 3H),

MS (FAB) m/z; 238 (MH⁻), 149

EXAMPLE 34 [{2-(1,3-benzodioxol-5-yl)ethyl}sulfonyl]propan-2-one##STR294##

4 g of [{2-(1,3-benzodioxol-5-yl)ethyl}thio]propan-2-one was dissolvedin 70 ml of chloroform. 8.1 g of 90% m-chloroperbenzoic acid was addedto the solution under cooling with ice/water and the mixture was stirredfor 2 h. 150 ml of chloroform and an aqueous sodium carbonate solutionwere added to the reaction mixture. After separation of the layers thusformed, the chloroform layer was washed with water there times and driedover anhydrous sodium sulfate. The solvent was distilled off and theresidue was recrystallized from ethyl acetate/isopropyl ether to obtain4.1 g of the intended compound in the form of colorless crystals.

mp.; 97°-99° C.

¹ H-NMR (90MHz, CDCl₃) δ; 2.39 (s, 3H), 2.88-3.47 (m, 4H), 3.92 (s, 2H),5.89 (s, 2H), 6.50-6.77 (m, 3H)

MS (FAB) m/z; 270 (M⁻), 149

EXAMPLE 35 5-{2-(ethylsulfonyl)ethyl}-1,3-benzodioxole ##STR295##

3.5 g of the intended compound in the form of colorless crystals wasobtained from 4 g of 5-(2-ethylthio)ethyl-1,3-benzodioxole in the samemanner as that of Example 34.

m.p.; 90°-91° C.

¹ H-NMR (90MHz, CDCl₃) δ; 1.38 (t, J=7.4 Hz, 3H), 2.92 (q,J=7.4Hz, 2H),3.00-3.22 (m, 4H), 5.93 (s, 2H), 6.57-6.81 (m, 3H)

MS (FAB) m/z; 243 (MH⁻), 149

EXAMPLE 36 5-{2-(1-Methylethylsulfonyl)ethyl)-1,3-benzodioxole##STR296##

4.0 g of the intended compound in the form of colorless crystals wasobtained from 4 g of 5-{2-(1-methylethyl)thio}ethyl-1,2-benzodioxole inthe same manner as that of Example 34.

mp.; 83°-85° C.

¹ H-NMR (90MHz, CDCl₃) δ; 1.39 (d, J=6.8Hz, 6H), 2.82-3.27 (m, 5H), 5.90(s, 2H), 6.44-6.78 (m, 3H)

MS m/z; 256 (MH⁻), 149

EXAMPLE 37 [{2-(1,3-Benzodioxol-5-yl)ethyl}sulfonyl]acetonitrile##STR297##

2.95 g of the intended compound in the form of colorless crystals wasobtained from 3 g of [{2-(1,3-benzodioxol-5-yl)ethyl}thio]acetonitrilein the same manner as that of Example 34.

m.p.; 93°-95° C.

¹ H-NMR (90MHz, CDCl₃) δ; 2.95-3.30 (m, 2H), 3.33-3.67 (m, 2H), 3.75 (s,2H), 5.91 (s, 2H), 6.56-6.88 (m, 3H)

MS m/z; 253 (M⁻), 149

COMPOUND GROUP (I-e) PREPARATIVE EXAMPLE 12-(1,3-Benzodioxol-5-yl)ethanethiol ##STR298##

750 g of 5-(2-bromoethyl)-1,3-benzodioxole was dissolved in 1 l ofethanol, followed by the addition of 312 g of thiourea. The mixture washeated under reflux on a boiling water bath for 2 hours and cooled,followed by the addition of a solution of 300 g of sodium hydroxide in 1l of water. The obtained mixture was heated under reflux on a boilingwater bath for 45 minutes and cooled, followed by the addition of 3 l ofwater. The obtained mixture was extracted with 5 l of ethyl acetate. Theextract was washed with dilute hydrochloric acid and then with wateruntil the washings become neutral, dried over anhydrous sodium sulfateand distilled at 40° C. to remove the solvent. About 570 g of a yellowoil was obtained. This oil was purified by silica gel columnchromatography (hexane/benzene=2:1) to obtain 310 g of the tile compoundas a colorless oil.

¹ H-NMR (90MHz, CDCl₃) δ; 1.36 (m, 1H), 2.6-2.9 (m, 4H), 5.87 (s, 2H),6.50-6.74 (m, 3H)

PREPARATIVE EXAMPLE 2 3-(1,3-Benzodioxol-5-yl)propanethiol ##STR299##

25 g of thioacetic acid was added to 53.5 g of safrole in portions,while stirring the mixture at a room temperature or under cooling withice/water. The reaction was carried out for 30 minutes. A solution of 20g of sodium hydroxide in a mixture comprising 100 ml of water and 200 mlof ethanol was added to the reaction mixture. The obtained mixture washeated under reflux for 20 minutes, cooled, neutralized with dilutesulfuric acid and extracted with 1 l of benzene. The extract was washedwith water and the benzene layer was dried over anhydrous sodium sulfateand purified by silica gel column chromatography (hexane) to obtain 42.8g of the title compound as a colorless oil.

¹ H-NMR (90MHz, CDCl₃) δ; 1.20-1.46 (m, 1H), 1.68-2.10 (m, 2H),2.34-2.78 (m, 4H), 5.84 (s, 2H), 6.44-6.75 (m, 3H)

PREPARATIVE EXAMPLE 3 2-(1,3-Benzodioxol-5-yl)-1-methylethanethiol##STR300##

5 g of anhydrous tin chloride was added to 100 g of safrole.Hydrochloric acid gas was passed though the mixture under cooling withice for 1.5 hours. 2 l of ethyl acetate was added to the reactionmixture, followed by the dissolution. The obtained mixture was washedwith water twice, dried over anhydrous sodium sulfate and distilled toremove the solvent. The residue was purified by silica gel columnchromatography (hexane/benzene=10:1) to obtain 41.7 g of5-(2-chloropropyl)-1,3-benzodioxole as a colorless oil. This oil wasdissolved in 150 ml of ethanol, followed by the addition of 48 g ofthiourea. The obtained mixture was heated under reflux for 7 days,cooled and filtered. A solution of 12.8 g of sodium hydroxide in 100 mlof water was added to the filtrate. The obtained mixture was heatedunder reflux for 2 hours, cooled and acidified with dilute sulfuricacid. 1 l of benzene and 1 l of water were added to the mixture to carryout the phase separation. The benzene layer was washed with water twice,dried over anhydrous sodium sulfate and distilled to remove the solvent.The residue was purified by silica gel column chromatography(hexane/benzene=10:1) to obtain 8.5 g of the title compound as acolorless oil.

¹ H-NMR (90MHz, CDCl₃) δ; 1.32 (d, J=6Hz, 3H), 1.54 (d, J=6Hz, 1H),2.61-2.84 (m, 2H), 2.90-3.35 (m, 1H), 5.86 (s, 2H), 6.46-6.76 (m, 3H)

EXAMPLE 1 (COMPOUND 1) 2-[{2-(1,3-Benzodioxol-5-yl)ethyl}dithio]ethanol##STR301##

35 g of 2-(1,3-benzodioxol-5-yl)ethanethiol and 75 g of2-mercaptoethanol were dissolved in 150 ml of ethanol, followed by theadditional of 43 g of iodine. The obtained mixture was stirred at a roomtemperature for 30 minutes, followed by the addition of 2 l of ethylacetate and 2 l of water. The mixture was separated into two phases. Theethyl acetate layer was washed with water twice, then with 1 l of a 1%aqueous solution of sodium hydrogensulfite twice and finally with waterthrice, dried over anhydrous sodium sulfate and filtered. The filtratewas distilled to remove the solvent. The residue was purified by silicagel column chromatography (benzen/ethyl acetate=10:1) to obtain 11.5 gof the title compound as a colorless oil.

¹ H-NMR (90MHz, CDCl₃) δ; 1.98 (t, J=7Hz, 1H), 2.85 (t, J=7Hz, 2H), 2.91(s, 4H), 3.89 (q, J=7Hz, 2H), 5.92 (s, 2H), 6.55-6.84 (m, 3H)

MS m/z; 258 (M⁻), 149

EXAMPLE 2 (COMPOUND 2) Bis{2-(1,3-benzodioxol-5-yl)ethyl}disulfide##STR302##

2 g of the title compound was prepared from 3 g of2-(1,3-benzodioxol-5-yl)ethanethiol as a colorless oil according to thesame procedure as that described in Example 1.

m.p.: 76° to 78° C.

¹ H-NMR (90MHz, CDCl₃) δ; 2.87 (s, 8H), 5.90 (s, 4H), 6.51-6.81 (m, 6H)

MS m/z; 362 (M⁻), 149

EXAMPLE 3 (COMPOUND 3) 2-[{2-(1,3-Benzodioxol-5-yl)ethyl}dithiol]ethylnicotinate ##STR303##

4 g of the 2-[{2-(1,3-benzodioxol-5-yl)ethyl}dithio]ethanol prepared inExample 1 was dissolved in a mixture comprising 20 ml of pyridine and 50ml of benzene to obtain a solution. 4 g of nicotinyl chloridehydrochloride was added to the solution. The obtained mixture was heatedunder reflux for 2 hours and poured into ice/water. The obtained mixturewas weekly basified with sodium hydrogencarbonate. Ethyl acetate wasadded to the mixture to carry out the phase separation. The ethylacetate layer was washed with water five times, dried over anhydroussodium sulfate and distilled to remove the solvent. The residue waspurified by silica gel column chromatography (hexane/ethyl acetate=3:1)to obtain 5.4 g of the title compound as a colorless oil.

¹ H-NMR (90MHz, CDCl₃) δ; 2.92 (s, 4H), 3.06 (t, J=7Hz, 2H), 4.62 (t,J=7Hz, 2H), 5.92 (s, 2H), 6.40-6.86 (m, 3H), 7.30-7.50 (m, 1H),8.20-8.41 (m, 1H), 8.68-8.85 (m, 1H), 9.14-9.34 (m, 1H)

MS m/z; 363 (M⁻), 149

EXAMPLE 4 (COMPOUND 4) 2-[{2-(1,3-Benzodioxol-5-yl)ethyl}dithio]ethylnicotinate hydrochloride ##STR304##

2.5 g of the 2-[{2-(1,3-benzodioxol-5-yl)ethyl}dithio]ethyl nicotinateprepared in Example 3 was dissolved in 20 ml of ethyl acetate, followedby the addition of a solution of hydrochloric acid in ethyl acetate. Themixture was distilled to remove the solvent. The residue was dissolvedin a methanol/ethanol mixture, followed by the filtration. The filtratewas concentrated and recrystallized from an ethanol/isopropyl ethermixture to obtain 2.5 g of the title compound as a colorless crystal.

m.p.: 113° to 122° C.

¹ H-NMR (90MHz, DMSO-d₆) δ;

2.66-3.00 (m, 4H), 3.11 (t,J=7Hz, 2H), 4.53 (t, J=7Hz,2H), 5.90 (s, 2H),6.43-6.92 (m, 3H), 7.62-7.91 (m, 1H), 8.36-8.60 (m, 1H), 8.78-9.02 (m,1H), 9.02-9.24 (m, 1H)

MS m/z; 363, 149

Elemental analysis: as C₁₇ H₁₇ NS₂.HCl

    ______________________________________                                                    C    H          N      Cl                                         ______________________________________                                        calculated (%)                                                                              51.06  4.54       3.50 8.87                                     found (%)     51.05  4.51       3.59 8.84                                     ______________________________________                                    

EXAMPLE 5 (COMPOUND 5) 2-[{3-(1,3-Benzodioxol-5-yl)propyl}dithio]ethanol##STR305##

8.4 g of the title compound was prepared from 27.8 g3-(1,3-benzodioxol-5-yl)propanethiol and 5.5 g of 2-mercaptoethanol as acolorless oil according to the same procedure as that described inExample 1.

¹ H-NMR (90MHz, CDCl₃) δ; 1.72-2.14 (m, 3H), 2.48-2.72 (m, 4H), 2.80 (t,J=7Hz, 2H), 3.84 (q, J=7Hz, 2H), 5.85 (s, 2H), 6.44-6.74 (m, 3H)

MS m/z; 272 (M⁻), 135

EXAMPLE 6 (COMPOUND 6) 3-(1,3-Benzodioxol-5-yl)propyl phenethyldisulfide ##STR306##

1.5 g of the title compound was prepared from 5 g of3-(1,3-benzodioxol-5-yl)propanethiol and 5 g of phenethyl mercaptan as acolorless oil according to the same procedure as that described inExample 1.

¹ H-NMR (90MHz, CDCl₃) δ; 1.70-2.20 (m, 2H), 2.50-2.80 (m, 4H), 2.92 (s,4H), 5.85 (s, 2H), 6.44-6.78 (m, 3H), 7.00-7.52 (m, 5H)

MS m/z; 332 (M⁻)

EXAMPLE 7 (COMPOUND 7) 2-[{3-(1,3-Benzodioxol-5-yl)propyl}dithio]ethylnicotinate ##STR307##

56.1 g of the title compound was prepared from 50 g of the2-[{3-(1,3-benzodioxol-5-yl)propyl}dithio]ethanol and 50 g of nicotinylchloride hydrochloride as a colorless oil according to the sameprocedure as that described in Example 3.

¹ H-NMR (90MHz, CDCl₃) δ; 1.72-2.12 (m, 2H), 2.65 (q, J=7Hz, 4H), 3.00(t, J=7Hz, 2H), 4.56 (t, J=7Hz, 2H), 5.85 (s, 2H), 6.42-6.70 (m, 3H),7.20-7.40 (m, 1H), 8.10-8.30 (m, 1H), 8.58-8.78 (m, 1H), 9.06-9.22 (m,1H)

MS m/z; 377 (M⁺)

EXAMPLE 8 (COMPOUND 8) 2-[{3-(1,3-Benzodioxol-5-yl)propyl}dithio]ethylnicotinate hydrochloride ##STR308##

48.5 g of the title compound was prepared from 46.1 g of2-[{3-(1,3-benzodioxol-5-yl)propyl}dithio]ethyl nicotinate as acolorless crystal according to the same procedure as that described inExample 4.

m.p.: 105° to 110° C.

¹ H-NMR (90MHz, DMSO-d₆) δ; 1.68-2.08 (m, 2H), 2.71 (q, J=7Hz, 4H), 3.13(t, J=7Hz, 2H), 4.58 (t, J=7Hz, 2H), 5.96 (s, 2H), 6.54-6.87 (m, 3H),7.69-7.90 (m, 1H),

8.44˜8.64 (m, 1H), 8.87˜9.02 (m, 1H), 9.12˜9.24 (m, 1H) ·MS m/z; 377

Elemental analysis: as C₁₈ H₁₉ O₄ NS₂ ·HCl

    ______________________________________                                                    C    H          N      Cl                                         ______________________________________                                        calculated (%)                                                                              52.23  4.87       3.38 8.56                                     found (%)     52.32  4.80       3.47 8.58                                     ______________________________________                                    

EXAMPLE 9 (COMPOUND 9)

3-(1,3-Benzodioxol-5-yl)propyl nonyl disulfide ##STR309##

6.2 g of the title compound was prepared from 10 g of3-(1,3-benzodioxol-5-yl)propanethiol and 5 g of nonyl mercaptan as acolorless oil according to the same procedure as that described inExample 1.

·¹ H-NMR(90 MHz, CDCl₃)δ;

0.74˜1.02 (m, 3H), 1.08˜1.48(bs, 14H), 1.80 ˜2.12(m, 2H), 2.50˜2.76 (m,6H), 5.86(s, 2H), 6.46˜6.75(m, 3H) ·MS m/z; 354 (M⁻)

EXAMPLE 10 (COMPOUND 10) 2-[{(1,3-Benzodioxol-5-yl)methyl}dithio]ethylnicotinate ##STR310##

2.8 g of the title compound was prepared from 2 g of2-[{(1,3-benzodioxol-5-yl)methyl}dithio]ethanol and 2.2 g of nicotinylchloride hydrochloride as a colorless oil according to the sameprocedure as that described in Example 3.

·¹ H-NMR(90 MHz, CDCl₃) δ;

2.76(t, J=7 Hz, 2H), 3.82(s, 2H), 4.45 (t,J=7 Hz, 2 H), 5.89 (s, 2H),6.52˜6.91 (m, 3H), 7.12˜7.42(m, 1H), 8.10˜8.34(m, 1H), 8.64˜8.87 (m,1H), 9.07˜9.28(m, 1H) ·MS m/z; 349(M⁻)

EXAMPLE 11 (COMPOUND 11)Bis{2-(1,3-benzodioxol-5-yl(-1-methylethyl}disulfide ##STR311##

3.5 g of the title compound was prepared from 4 g of2-(1,3-benzodioxol-5-yl)-1-methylethanethiol as a colorless oilaccording to the same procedure as that described in Example 1.

¹ H-NMR(90 MHz, CDCl₃) δ;

1.24(d, J=7 Hz, 6H), 2.32˜2.71(m, 2H), 2.72 ˜3.16(m, 4 H), 5.91 (s, 4H),6.48˜6.82(m, 6 H)

·MS m/z; 390 (M⁻)

EXAMPLE 12 (COMPOUND 12)2-[{2-(1,3-Benzodioxol-5-yl)-1-methylethyl}dithio]-ethanol ##STR312##

5.0 g of the title compound was prepared from 8.4 g of2-(1,3-benzodioxol-5-yl)-1-methylethanethiol and 2.24 g of2-mercaptoethanol as a colorless oil according to the same procedure asthat described in Example 1.

¹ H-NMR(90 MHz, CDCl₃) δ; 1.27 (d, J=7 Hz, 3H), 1.80˜2.20 (br, 1H), 2.40˜2.80(m, 1H), 2.63˜3.25(m, 4H), 3.60˜4.10 (br, 2H), 5.90 (s, 2H),6.50˜6.88(m, 3H) ·MS m/z; 272 (M⁻)

Compound Group (I-f)

PREPARATIVE EXAMPLE 1 2-)1,3-Benzodioxol-5-yl)-2-propanol ##STR313##

About 600 ml of a 1.5 M solution of methyllithium in ether was added to500 ml of tetrahydrofuran to obtain a mixture. A suspension of 93.45 gof 5-acetyl-1,3-benzodioxole in 900 ml of tetrahydrofuran was added tothe mixture, while keeping it at -20° C. by cooling and the obtainedmixture was stirred as such for one hour. Water was added to thereaction mixture and the obtained mixture was extracted with ethylacetate. The organic layer was washed with a saturated aqueous solutionof common salt and dried over anhydrous magnesium sulfate. The resultingmixture was filtered and the filtrate was concentrated to obtain 97 g ofthe title compound as an oil.

·¹ H-NMR(90 MHz, CDCl₃) δ;

1.54(s, 6H), 1.72(bs, 1H), 5.88(s, 2H), 6.6˜7.0 (m, 3)

PREPARATIVE EXAMPLE 2 2-(1,3-Benzodioxol-5-yl)propene ##STR314##

14.52 g of 2-(1,3-benzodioxol-5-yl)-2-propanol was dissolved in 200 mlof benzene, followed by the addition of a catalytic amount ofp-toluenesulfonic acid monohydrate. The obtained mixture was heatedunder reflux in a short-neck Kieldahl flask fitted with a Dean-Starkreflux condenser for 2.5 hours. The reaction mixture was washed with asaturated aqueous solution of sodium hydrogencarbonate and a saturatedaqueous solution of common salt successively, dried over anhydrousmagnesium sulfate and filtered. The filtrate was concentrated to obtain14.33 g of the title compound as an oil.

·¹ H-NMR(90 MHz, CDCl₃) δ;

2.08(bs, 3H), 4.8˜5.0 (m, 1H), 5.19(bs, 1H), 5.89(s, 2H), 6.5˜7.0(m, 3H)

PREPARATIVE EXAMPLE 3 1-(6-Methyl-1,3-benzodioxol-5-yl)ethanol##STR315##

32 ml of a 1.4 M solution of methyllithium in diethyl ether wasdissolved in 50 ml of anhydrous tetrahydrofuran. The obtained solutionwas cooled to -40° C. in a nitrogen atmosphere, followed by the additionof 5.0 g of solid (6-methyl-1,3-benzodioxol-5-yl(carboxaldehyde. Themixture was heated to a room temperature over a period of one hour,followed by the addition of water. The obtained mixture was extractedwith ether and the obtained organic layer was washed with an aqueoussolution of common salt, dried over magnesium sulfate and distilled toremove the solvent. The obtained white solid was recrystallized fromdiisopropyl ether/n-hexane to obtain 2.8 g of the title compound as acolorless crystal.

m.p.: 61°to 62° C. ·¹ -NMR(90MHz, CDCl₃) δ;

1.39 (d, J=7 Hz, 3H), 1.72(bs,1), 2.22(s, 3H), 4.99(m, 1H), 5.83(s, 2H),6.53(s, 1H), 6.94(s, 1H)

PREPARATIVE EXAMPLE 4 1-(6-Methyl-1,3-benzodioxol-5-yl)-1-propanol##STR316##

A solution of 2.0 g of (6-methyl-1,3-benzodioxol-5-yl)-carboxaldehyde in15 ml of anhydrous tetrahydrofuran was dropwise added at a roomtemperature to a Grignard reagent prepared from 0.32 g of magnesiumribbon, 20 ml of anhydrous tetrahydrofuran and 1.4 g of bromoethane,followed by stirring for 2 hours. A saturated aqueous solution ofammonium chloride was added to the reaction mixture and the obtainedmixture was distilled to remove the solvent. The residue was extractedwith ethyl acetate and the organic layer was dried over magnesiumsulfate and concentrated in a vacuum. The residue was purified by silicagel column chromatography (ethyl acetate/hexane=2:8) to obtain 2.27 g ofthe title compound as a colorless crystal.

m.p.: 71° to 72° C.

·¹ H-NMR(90 MHz, CDCl₃) δ:

0.92(, J=7 Hz, 3 H), 1.68˜1.92 (m, 2H), 1.80(bs, 1H), 2.20(s, 3H),4.72(t, J=7 Hz, 1H), 5.82(s, 2H), 6.52(s, 1H), 6.88(s, 1H)

PREPARATIVE EXAMPLE 5 1-(6-Ethyl-1,3-benzodioxol-5-yl)-1-propanol##STR317##

A solution of 3.2 g of (6-ethyl-1,3-benzodioxol-5-yl)-carboxaldehyde in10 ml of anhydrous tetrahydrofuran was dropwise added at a roomtemperature to a Grignard reagent prepared from 0.54 g of magnesiumribbon, 10 ml of anhydrous tetrahydrofuran and 2.4 g of bromoethane, tocarry out the reaction at the same temperature for 2 hours. A saturatedaqueous solution of ammonium chloride was added to the reaction mixture.The obtained mixture was distilled to remove the solvent and the residuewas extracted with ethyl acetate. The organic layer was dried overmagnesium sulfate and concentrated in a vacuum to obtain 3.9 g of acrude alcohol as a yellow oil. This oil was used as such in thesubsequent reactions.

·¹ H-NMR(90 MHz, CDCl₃) δ:

0.96(t, J=7 Hz, 3 H), 1.18 (t, J=7 Hz, 3H), 1.72(m, 3H), 2.32˜2.80 (m,2H), 4.76(t, J=7 Hz, 1H), 5.84(s, 2H), 6.58(s, 1H), 6.88 (s, 1H)

PREPARATIVE EXAMPLE 6 2-(1,3-Benzodioxol-5-yl)-2-butanol ##STR318##

15 ml of tetrahydrofuran and a catalytic amount of iodine were added to340 mg of magnesium ribbon to obtain a mixture. 1.59 g of bromoethanewas gradually added to the mixture in a stream of nitrogen in such a waythat the reaction system was mildly refluxed. The resulting mixture washeated under reflux for 30 minutes and cooled, followed by the additionof a solution of 2 g of 5 -acetyl-1,3-benzodioxole in tetrahydrofuran.The obtained mixture was stirred at a room temperature for 20 minutes,followed by the addition of a saturated aqueous solution of ammoniumchloride and water. The obtained mixture was extracted with ethylacetate. The organic layer was washed with a saturated aqueous solutionof common salt, dried over ahydrous magnesium sulfate and filtered. Thefiltrate was distilled to remove the solvent. 2.27 g of the titlecompound was obtained as a crude oil.

PREPARATIVE EXAMPLE 7 5-Chloromethyl-6-isopropyl-1,3-benzodioxole##STR319##

A mixture comprising 30 g of 37% formalin, 13 ml of concentratedhydrochloric acid and 100 m l of ethyl acetate was heated to 55° C.,while passing hydrochloric acid gas through the mixture. A solution of7.5 g of 5-isopropyl-1,3-benzodioxole in 20 ml of ethyl acetate wasdropwise added to the resulting mixture and the obtained mixture wasstirred as such for 2.5 hours and cooled, followed by the addition ofbenzene. The obtained mixture was washed with water, dried overanhydrous magnesium sulfate and filtered. The filtrate was concentratedto obtain 10.22 g of the title compound as a crude oil.

19 ¹ H-NMR(90 MHz, CDCl₃) δ;

1.18(d, J=7.2 Hz, 6H), 3.31 (sept, J=7.2 Hz, 1H), 5.88(s, 2H), 6.70(s,1), 6.91(s, 1H)

PREPARATIVE EXAMPLE 8 5-Bromo-6-isopropyl-1,3-benzodioxole ##STR320##

2.94 g of 5-isopropyl-1,3-benzodioxole was dissolved in 30 ml of carbontetrachloride to obtain a solution. A solution of 3.15 g of bromine in 5ml of carbon tetrachloride was dropwise added to the solution at atemperature of -5° to 5° C. The obtained mixture was stirred at 10° C.for 8.5 hours. Nitrogen gas was passed through the resulting mixture,followed by the addition of a saturated aqueous solution of sodiumhydrogencarbonate and an aqueous solution of sodium thiosulfate. Theobtained mixture was extracted with chloroform and the organic layer waswashed with a saturated aqueous solution of common salt, dried overanhydrous sodium sulfate and filtered. The filtrate was concentrated toobtain 4.38 g of the title compound as a crude oil.

·¹ H-NMR(90 MHz, CDCl₃) δ;

1.18(d, J=7.2 Hz, 6H), 3.31 (sept, J=7.2 Hz, 1H), 5.58 (s, 2H), 6.70 (s,1H), 6.91(s, 1H)

PREPARATIVE EXAMPLE 9 5-(6-Isopropyl-1,3-benzodioxole)carboxaldehyde##STR321##

7.8 ml of a 1.6 M solution of n-butyllithium in hexane was added to asolution of 2.34 g of 5-bromo-6-isopropyl-1,3-benzodioxole (crude oil)in 50 ml of anhydrous ether at 31 40° C. the obtained mixture was heatedto -10° C. and cooled again to -50° C., followed by the addition of 4.48ml of N,N-dimethylformamide. The obtained mixture was heated understirring to raise the temperature thereof to 0° C. slowly. Then, theresulting mixture was acidified with 1 N hydrochloride acid, stirred for30 minutes and extracted with ethyl acetate. The organic layer waswashed with a saturated aqueous solution of common salt, dried overanhydrous magnesium sulfate and filtered. The filtrate was distilled toremove the solvent. The residue was purified by silica gel columnchromatography (hexane) to obtain 1.40 g of the title compound as acolorless oil.

·¹ H-NMR(90 MHz, CDCl₃) δ;

1.28(d, J=6.5 Hz, 6H), 3.84 (sept, J=6.5 Hz, 1H), 5.96 (s, 2H), 6.81 (s,1H), 7.23(s, 1H)

PREPARATIVE EXAMPLE 10 α-(6-Isopropyl-1,3-benzodioxole-5-yl)benzylalcohol ##STR322##

8.1 ml of a 2.0 M solution of phenyllithium in a cyclohexane/diethylether (7:3) mixture was added to a solution of 2.08 g of5-(6-isopropyl-1,3-benzodioxol-5-yl)carboxaldehyde in anhydrous ether at-60° C. The obtained mixture was stirred overnight in such a way thatthe temperature thereof rose to a room temperature slowly. Ice/water wasadded to the resulting mixture and the obtained mixture was extractedwith ethyl acetate. The organic layer was washed with a saturatedaqueous solution of common salt, dried over anhydrous magnesium sulfateand filtered. The filtrate was distilled to remove the solvent. Theresidue was purified by silica gel column chromatography (ethylacetate/hexane=2:98) to obtain 2.49 g of the title compound as acolorless prismatic crystal.

·¹ H-NMR(90 MHz, CDCl₃) δ;

1.03(d, J=6.8 Hz, 3H), 1.18(d, J=6.8 Hz, 3H), 2.03 (d, J=1.8 Hz, 1H),3.18 (m, 1H), 5.86(s, 2H), 6.05(d, J=1.8 Hz, 1H), 6.72(s, 1H), 6.84(s,1H), 7.05˜7.4(m, 5H)

PREPARATIVE EXAMPLE 11 5-Cyanomethyl-6-Isopropyl-1,3-benzodioxole)##STR323##

6.9 g of 5-chloromethyl-6-isopropyl-1,3-benzodioxole was dissolved in100 ml of dimethyl sulfoxide, followed by the addition of3.12 g ofsodium cyanide. The obtained mixture was stirred at a room temperaturefor 3 hours and distilled to remove the solvent. Ethyl acetate was addedto the residue and the obtained mixture was washed with water and asaturated aqueous solution of common salt successively, dried overanhydrous magnesium sulfate and filtered. The filtrate was concentratedto obtain 6.26 g of the title compound as a crude oil.

·¹ H-NMR(90 MHz, CDCl₃) δ;

1.21(d, J=7.2 Hz, 6H), 2.96 (sept, J=7.2 Hz, 1H), 3.60 (s, 2H), 5.88 (s,2H), 6.73(bs, 2H)

PREPARATIVE EXAMPLE 12 6-Isopropyl-1,3-benzodioxole-5-yl)acetic acid##STR324##

6.22 g of 5-chloromethyl-6-isopropyl-1,3-benzodioxole (crude oil) wasdissolved in 120 ml of dimethyl sulfoxide, followed by the addition of40 g of water and 12.24 g sodium hydroxide. The obtained mixture wasstirred for 20 hours, while keeping the temperature of an oil bath at100° C. The reaction mixture was concentrated, followed by the additionof water. The obtained mixture was washed with ethyl acetate. Theaqueous layer was acidified with concentrated hydrochloric acid andextracted with chloroform. The organic layer was washed with a saturatedaqueous solution of common salt, dried over anhydrous magnesium sulfateand filtered. The filtrate was concentrated to obtain 6.31 g of thetitle compound as a crude crystal.

·¹ H-NMR(90 MHz, CDCl₃) δ;

1.17(d, J=6.5 Hz, 6H), 2.99 (sept, J=6.5 Hz, 1H), 3.58 (s, 2H), 5.85 (s,2H), 6.60(s, 1H) 6.72(s, 1H)

PREPARATIVE EXAMPLE 13 2-(6-Isopropyl-1,3-benzodioxol-5-yl)ethanol##STR325##

A solution of 6.25 g of (6-isopropyl-1,3-benzodioxol-5-yl)acetic acid(crude crystal) in 30 ml of tetrahydrofuran was dropwise added to asuspension of 1.6 g of lithium aluminum hydride in 40 ml oftetrahydrofuran under cooling with ice. The obtained mixture was stirredovernight. 1.6 ml of water, 1.6 ml of a 15% aqueous solution of sodiumhydroxide and 4.8 ml of water were added to the resulting mixturesuccessively under cooling with ice. The obtained mixture was filteredand the filtrate was concentrated. The residue was purified by silicagel column chromatography to obtain 4.51 g of the title compound as acolorless oil.

·¹ H-NMR(90 MHz, CDCl₃) δ;

1.19(d, J=6.8 Hz, 6H), 1.3˜1.6 (br, 1H), 2.82(t, J=6.8 Hz, 2H), 3.10(sept, J=6.8 Hz, 1H), 3.5˜3.9 (br, 2H), 5.84(s, 2H), 6.59 (s, 1),6.72(s, 1H)

PREPARATIVE EXAMPLE 14 (6-Benzyl-1,3-benzodioxol-5-yl)acetic acid##STR326##

6.0 g of 5-benzyl-1,3-benzodioxole was dissolved in 100 ml of ethylacetate to obtain a solution. This solution was dropwise added at 55° C.to a mixture comprising 10 ml of concentrated hydrochloric acid, 20 mlof ethyl acetate and 22 g of 37% formalin into which hydrogen chloridegas had been bubbled. The reaction was carried out at the sametemperature for 1.5 hours. The reaction mixture was washed with waterfour times, dried over magnesium sulfate and concentrated in a vacuum toobtain 10.6 g of a crude chloro derivative as a pale yellow oil.

7.1 g of the crude chloro derivative (unpurified) was dissolved in 50 mlof dimethyl sulfoxide, followed by the addition of 2.0 g of well-groundsodium cyanide. The reaction was carried out for 2 hours. Water wasadded to the reaction mixture, followed by the extraction withchloroform. The organic layer was washed with water twice, dried overmagnesium sulfate and concentrated in a vacuum to obtain 4.4 g of acrude cyano derivative as a yellow oil.

This cyano derivative and 7 g of sodium hydroxide were dissolved in amixture comprising 20 ml of ethanol and 20 ml of water. The obtainedsolution was heated under reflux for 20 hours. After the completion ofthe reaction, the reaction mixture was distilled in a vacuum to removethe ethanol, followed by the addition of 200 ml of water. The obtainedmixture was washed with ether. The aqueous layer was acidified with 6 Nhydrochloric acid and extracted with chloroform. The organic layer waswashed with a saturated aqueous solution of common salt, dried overmagnesium sulfate and concentrated in a vacuum to obtain a brown solid.This solid was recrystallized from ethyl acetate to obtain 1.83 g of thetitle compound as a pale yellow needle.

m.p.: 116° to 117° C.

·¹ H-NMR(90 MHz, CDCl₃) δ;

3.48(s, 2H), 3.88 (s, 2H), 5.86(s, 2H), 6.56(s, 1H), 6.64(s, 1H)6.80--7.40(m, 5H), 8.40˜10.0(bs, 1H)

PREPARATIVE EXAMPLE 15 2-(6-Benzyl-1,3-benzodioxol-5-yl)ethanol##STR327##

A solution of 1.82 g of (6-benzyl-1,3-benzodioxol-5-yl) acetic acid in22 ml of anhydrous tetrahydrofuran was dropwise added at 0° C. to asuspension of 0.38 g of lithium aluminum hydride in anhydroustetrahydrofuran. The obtained mixture was warmed to a room temperatureto carry out the reaction for 4 hours, followed by the addition ofwater. The mixture was filtered to remove the precipitate. The filtratewas concentrated in a vacuum to obtain a yellow oil residue. Thisresidue was purified by silica gel column chromatography (ethylacetate/hexane=2:8) to obtain 1.42 g of the title compound as acolorless crystal.

m.p.: 64° to 65° C.

·¹ H-NMR(90 MHz, CDCl₃) δ;

2.76(t, J=7 Hz, 2H), 3.64(m, 2H), 3.90(s, 2H), 5.86(s, 2H), 6.56(s, 1H),6.66(s, 1H), 6.80˜7.34(m, 5)

EXAMPLE 1 [{1-(1,3-Benzodioxol-5-yl)butyl}thio]acetic acid ##STR328##

A mixture comprising 103 g of 1-(1,3-benzodioxol-5-yl)-1butanol, 73.3 gof mercaptoacetic acid, 0.1 g of D-10-camphorsulfonic acid and 500 ml ofbenzene was heated under reflux for 2 hours, followed by the addition of2000 ml of ether. The obtained mixture was washed with water andextracted with 750 ml and then 100 ml of 1 N sodium hydroxidesuccessively. The extracts were combined, washed with ether andchloroform successively, acidified with concentrated hydrochloric acidand extracted with ethyl acetate (800 ml and 400 ml). The extracts werecombined, washed with water, dried over magnesium sulfate andconcentrated in a vacuum to obtain 132 g of a crude product. This crudeproduct was purified by silica gel chromatography (ethylacetate/hexane/formic acid =100:900:1) to obtain 127 g of a colorlessoil. This oil was crystallized from n-hexane to obtain 115 g of thetitle compound as a white crystalline powder.

m.p.: 59° to 61° C.

·¹ H-NMR(90 MHz, CDCl₃) δ;

0.88(m, 3H), 1.12˜1.52(m, 2), 1.78˜1.94(m, 2H), 2.92 and 3.03(ABq, J=15Hz , 2H), 3.92(t, J=7 Hz, 1H), 5.92(s, 2H), 6.68˜6.80(m, 3H)

EXAMPLE 2 [{1-(1,3-Benzodioxol-5-yl)-1-methylethyl}thio]acetic acid##STR329##

600 ml of benzene, 59.5 g of mercaptoacetic acid and a catalytic amountof D-100camphorsulfonic acid were added to 97 g of2-(1,3-benzodioxol-5-yl)-2-propanol. The obtained mixture was heatedunder reflux for 4 hours and distilled to remove the solvent. The pH ofthe residue was adjusted to 10 with a 1N aqueous solution of sodiumhydroxide. The resulting mixture was washed with ethyl acetate. 4Nhydrochloric acid was added to the mixture under cooling with ice toacidify the aqueous layer. The resulting mixture was extracted withchloroform. The organic layer was washed with water, dried overanhydrous magnesium sulfate and filtered. The filtrate was concentratedto obtain a crude crystal. This crude crystal was recrystallized fromdiisopropyl ether to obtain 62.70 g of the title compound as a colorlesscrystal.

The above procedure was repeated except that 38.73 g of2-(1,3-benzodioxol-5-yl)propene was used instead of the correspondingpropanol to obtain 37.32 g of the title compound.

m.p.: 78.5° to 80° C.

·¹ H-NMR(90 MHz, CDCl₃) δ;

1.68(s, 6H), 2.29(s, 2H), 5.88(s, 2H), 6.64(d, J=8.3 Hz, 1H), 6.86(dd,J=8.3 Hz, 2.5 Hz, 1H), 6.99(d, J=2.5 Hz, 1H), 8.0˜9.0(br, 1)

EXAMPLE 3 [{1-(1-Methyl-1,3-benzodioxol-5-yl)-ethyl}thio]acetic acid##STR330##

3.7 g of mercaptoacetic acid and a catalytic amount ofD-10-camphorsulfonic acid were added to 3.2 g of1-(6-methyl-1,3-benzodioxol-5yl)(ethanol, followed by the addition of100 ml of benzene. The obtained mixture was heated under reflux for onehour, washed with water and extracted with a 1N aqueous solution ofsodium hydroxide. The aqueous layer was washed with ethyl acetate,acidified with 1 N hydrochloric acid and extracted with chloroform. Theorganic layer was dried over magnesium sulfate and distilled to removethe solvent. The obtained crystalline residue was recrystallized fromdiisopropyl ether to obtain 4.2 g of the title compound as a colorlesscrystal.

m.p.: 93.5° to 94.5° C.

·¹ H-NMR(90 MHz, CDCl₃) δ;

1.51(d, J=7 Hz, 3H), 2.26(s, 3H), 2.92 and 3.12(ABq, J=16 Hz, 2H),4.39(q, J=7 Hz, 1H), 5.85(s, 2H), 6.54(s, 1H), 6.94(s, 1H), 10.12(m,1H).

EXAMPLE 4 [{1-(1-Methyl-1,3-benzodioxol-5-yl)propyl}thio]acetic acid##STR331##

2.27 g of 1-(6-methyl-1,3-benzodioxol-5-yl)-1-propanol, 0.1 g ofp-toluenesulfonic acid and 1.52 g of mercaptoacetic acid were dissolvedin 80 ml of benzene to obtain a solution. This solution was heated underreflux for 12 hours, while removing generated water. The reactionmixture was poured into water. The aqueous layer was basified and washedwith ether. The aqueous layer was acidified and extracted withchloroform. The organic layer was washed with water, dried overmagnesium sulfate and concentrated in a vacuum to obtain a pale yellowsolid. This solid was purified by silica gel column chromatography(ethyl acetate/hexane=2:8) to obtain 2.83 g of the title compound as awhite crystal.

m.p.: 98° to 99° C.

·¹ H-NMR(90 MHz, CDCl₃) δ;

0.88(t, J=7 Hz, 3H), 1.60˜2.12(m, 2), 2.24(s, 3H), 2.96 and 3.08(ABq,J=14 Hz, 2H), 4.26(dd, J=9 Hz, 1H), 5.92(s, 2H), 6.62 (s, 1H), 6.98(s,1H

EXAMPLE 5 [{1-(6-Ethyl-1,3-benzodioxol-5-yl)propyl}thio]acetic acid##STR332##

4.0 g of ethyl [{1-(6-ethyl-1,3-benzodioxol-5-yl)-propyl}thio]acetateand 2.6 g of sodium hydroxide were dissolved in a mixture comprising 20ml of water and 20 ml of ethanol. The obtained solution was heated underreflux for 2 hours and distilled to remove the ethanol. The residue waswashed with ether. The aqueous layer was acidified and extracted withchloroform. The extract was washed with water, dried over magnesiumsulfate and concentrated in a vacuum. The residue was purified by silicagel column chromatography (ethyl acetate/hexane=2:8) to obtain 2.8 g ofthe title compounds as a colorless crystal.

m.p.: 88° to 89° C.

·¹ H-NMR(90 MHz, CDCl₃) δ;

0.92(t, J=7 Hz, 3H), 1.16(t, J=7 Hz, 3), 1.56˜2.12(m, 2H), 2.24˜2.76(m,2H), 2.95 and 3.08(ABq, J=16 Hz, 2H), 4.20(t, J=7 Hz, 1H), 5.88(s, 2H),6.58(s, 1H), 6.90 (s, 1H), 9.72(bs, 1H)

EXAMPLE 6 [{(6-Methyl-1,3-benzodioxol-5-yl)methyl}thio]acetic acid##STR333##

A suspension of 6.0 g of 5-chloromethyl-6-methyl-1,3-benzodioxole, 6.0 gof mercaptoacetic acid and 6.5 g of sodium hydroxide in 130 ml of 50%aqueous ethanol was heated under reflux for one hour and concentrated,followed by the addition of water. The mixture was washed with ethylacetate. The aqueous layer was acidified with 1N hydrochloric acid andextracted with chloroform. The organic layer was dried over magnesiumsulfate and distilled to remove the solvent. The residue waschromatographed over a silica gel column and eluted with chloroform toobtain a crude crystal. This crude crystal was recrystallized fromdiisopropyl ether to obtain 1.6 g of the title compound as a colorlesscrystal.

m.p.: 90° to 92° C.

·¹ H-NMR(90 MHz, CDCl₃) δ;

2.30(s, 3H), 3.14(s, 2H), 3.76(s, 2H), 5.86(s, 2H), 6.60(s, 1H), 6.70(s,1H)

EXAMPLE 7 [{1-(1,3-Benzodioxol-5-yl)-2-methylpropyl}thio]acetic acid##STR334##

A mixture comprising 2 g of1-(1,3-benzodioxol-5-yl)-2-methyl-1-propanol, 1.3 g of mercaptoaceticacid, a catalytic amount of p-toluenesulfonic acid and 50 ml of benzenewas heated under reflux for 5.5 hours, followed by the addition of ethylacetate. The mixture was washed with water and extracted with a 2Naqueous solution of sodium hydroxide. The aqueous layer was washed withchloroform, acidified with dilute hydrochloric acid and extracted withethyl acetate. The extract was washed with water, dried over anhydrousmagnesium sulfate and concentrated in a vacuum to obtain a residue. Thisresidue was purified by silica gel column chromatography(chloroform/methanol=20:1) to obtain 2.14 g of the title compound as acolorless oil.

·¹ H-NMR(90 MHz, CDCl₃) δ;

0.81(d, J=7.0 Hz, 3H), 1.09(d, J=7.0 Hz, 3H), 1.80˜2.23(m, 1H), 2.88 and3.01(ABq, J=15.1 Hz, 2H), 3.73(d, J=9.0 Hz, 1H), 5.89(s, 2H(,6.61˜6.89(m, 3H), 8.18˜8.69(bs, 1H)

EXAMPLE 8 Sodium [{1-(1,3-benzodioxol-5-yl)-2-methylpropyl}thio]-acetate##STR335##

3.99 ml of a 2N aqueous solution of sodium hydroxide was added to 2.14 gof [{1-(1,3-benzodioxol-5-yl)-2-methyl-1-propyl}thio]acetic acid toobtain a solution, followed by the addition of ethanol. The mixture wasdistilled to remove the solvent. Ether was added to the obtained residueto generate a precipitate. This precipitate was separated by filtrationand dried to obtain 2.2 g of the title compound as a white powder.

m.p.: 243° to 250° C. (decomp.)

·¹ H-NMR(90 MHz, CDCl₃) δ;

0.75(d, J=7.0 Hz, 3H), 1.01(d, J=7.0 Hz, 3H), 1.61˜2.22(m, 1H), 2.62 and2.70(ABq, J=13.5 Hz, 2H), 3.63(d, J=8.3 Hz, 1H), 5.97(s, 2H),6.50˜7.02(m, 3H) ·MS(FAB) m/z; 313(MNa⁻)

EXAMPLE 9 [{1-(1,3-Benzodioxol-5-yl)pentyl}thio]acetic acid ##STR336##

2.0 g of the title compound was obtained as a colorless oil from 2 g of1-(1,3-benzodioxol-5-yl)-1-pentanol according to the same procedure asthat described in Example 7.

·¹ H-NMR(90 MHz, CDCl₃) δ;

0.70˜0.93(m, 3H), 1.04˜1.54(m, 4H), 1.60˜2.02(m, 2H), 2.90 and 3.02(ABq,J= 14.4 Hz, 2H), 3.88(t, J=7 Hz, 1H), 5.90(s, 2H), 6.62˜6.90(m, 3H),6.62˜7.34(bs, 1H)

EXAMPLE 10 Sodium [{1-(1,3-benzodioxol-5-yl)pentyl}thio]acetate##STR337##

1.9 g of the title compound was prepared from 2.0 g of[{1-(1,30benzodioxol-5-yl)pentyl}thio]acetic acid as a white powderaccording to the same procedure as that described in Example 8.

m.p.: 232° to 242° C.

·¹ H-NMR(90 MHz, DMSO-d₆) δ;

0.62˜0.80(m, 3H), 0.94˜1.38(m, 4H), 1.54˜1.88(m, 2H), 2.67 and 2.75(ABq,J=13.3 Hz, 2H), 3.83(t, J=7.0 Hz, 1H), 5.97(s, 2H), 6.60˜6.90(m, 3H) ·MS(FAB) m/z; 327(MNa⁻)

EXAMPLE 11 [{1-(1,3-Benzodioxol-5-yl)-1-methylpropyl}thio]acetic acid##STR338##

50 ml of benzene, 1.29 g of mercaptoacetic acid and a catalytic amountof p-toluenesulfonic acid monohydrate were added to 2.27 g of2-(1,3-benzodioxol-5-yl)-2-butanol (crude oil). The obtained mixture washeated under reflux for 11 hours and cooled, followed by the addition ofbenzene. The obtained mixture was washed with water, followed by theaddition of a 1N aqueous solution of sodium hydroxide. The alkalinelayer was separated, washed with ethyl acetate, acidified withconcentrated hydrochloric acid and extrated with chloroform. The organiclayer was washed with water, dried over anhydrous magnesium sulfate andfiltered. The filtrate was distilled to remove the solvent. The residuewas purified by silica gel column chromatography (chloroform) to obtain1.11 g of the title compound as a colorless oil.

·¹ H-NMR(90 MHz, CDCl₃) δ;

0.82(d, J=7.2 Hz, 3), 1.66(s, 3H), 1.7˜2.1 (m, 2H), 5.90(s, 2H), 6.65(d,J=7.9 Hz, 1H), 6.82(dd, J=7.9 Hz and 1.8 Hz, 1H), 6.96(d, J=1.8 Hz, 1H),7.4˜8.6(br, 1H)

EXAMPLE 12 Sodium[{1-(1,3-benzodioxol-5-yl)-1-methylpropyl}thio]-acetate ##STR339##

1.00 g of the title compound was obtained from 1.04 g of[{1-(1,3-benzodioxol-5-yl)-1-methylpropyl}-thio]acetic acid as a whitepowder according to the same procedure as that described in Example 8.

m.p.: >280° C.

·¹ H-NMR(90 MHz, CDCl₃) δ;

0.72(bt, J=7.2 Hz, 3H), 1.52(s, 3H), 1.6˜2.1(m, 2H), 2.70(ABq, J=13.3Hz, .increment.ν=20.5), 5.97(s, 2H), 6.5˜7.1(m, 3H) ·MS(FAB) m/z;313(MNa⁻), 291(MH³¹ )

EXAMPLE 13 [[1-(1,3-Benzodioxol-5-yl)-2-phenyl}thio]acetic acid##STR340##

5.5 g of the title compound was obtained from 5.0 g of(1-(1,3-benzodioxol-5-yl)-2-phenyl}ethan-1-ol as a colorless needleaccording to the same procedure as that described in Example 7.

m.p.: 99° to 100° C.

·¹ H-NMR(90 MHz, CDCl₃) δ;

2.92 and 3.04(ABq, J=14.4 Hz, 2H), 2.88˜3.36(m, 2H), 4.20(t, J=7.2 Hz,1H), 5.90(s, 2H), 6.48˜6.76(m, 2H), 6.84(s, 1H), 6.88˜7.36(m, 5H),9.50˜10.00(br, 1H)

EXAMPLE 14 Sodium [[1-(1,3-benzodioxol-5-yl)-2-phenyl}thio]acetate##STR341##

1.7 g of the title compound was obtained from 2.0 g of[[1-{1-1,3-benzodioxol-3-yl)-2-phenyl}ethyl]-thio]acetic acid as a whitepowder according to the same procedure as that described in Example 8.

m.p.: 201° to 215° C. (decomp.)

·¹ H-NMR(90 MHz, CDCl₃) δ;

2.71 and 2.79(ABq, J=13.9 Hz, 2H), 3.00 (dd, J=9.2 Hz and 13.7 Hz, 1H),3.12(dd, J=6.2 Hz and 13.9 Hz, 1H), 4.19(dd, J=6.2 Hz and 9.5 Hz, 1H),5.95(m, 2H), 6.64(dd, J=1.5 Hz and 8.1 Hz, 1H), 5.95(m, 2H), 6.64(dd,J=6.865(d, J=1.8 Hz, 1H), 7.08˜7.19(m, 5H) ·MS(FAB) m/z; 339(MH⁻)

EXAMPLE 15 [{1-(6-Methyl-1,3-benzodioxol-5-yl)butyl}thio]acetic acid##STR342##

A solution of 5.0 g of (6-methyl-1,3-benzodioxol-5-yl)-carboxaldehyde in20 ml of tetrahydrofuran was dropwise added at a room temperature to aGrignard reagent prepared from 0.86 g of magnesium ribbon, 10 ml oftetrahydrofuran and 4.4 g of 1-bromopropane. The obtained mixture wasstirred at a room temperature for one hour, followed by the addition ofa saturated aqueous solution of ammonium chloride. The obtained mixturewas extracted with ether. The organic layer was washed with an aqueoussolution of common salt, dried over magnesium sulfate and distilled toremove the solvent. 5.6 g of (6-methyl-1,3-benzodioxol-5-yl)-butan-1-olwas obtained.

m.p.: 65.5° to 66.5° C.

·¹ H-NMR(90 MHz, CDCl₃) δ;

0.92 (m, 3H), 1.16˜1.80(m, 5H), 2.21(s, 3H), 4.83(m, 1H), 5.85(s, 2H),6.55(s, 1H), 6.92(s, 1H)

This product was used in the following reaction without being purified.

A solution of 5.6 g of (6-methyl-1,3-benzodioxol-5-yl)butan-1-ol, 4.8 gof mercaptoacetic acid and a catalytic amount of D-10-camphorsulfonicacid in 60 ml of benzene was heated under reflux for 3 hours, followedby the addition of ethyl acetate. The obtained mixture was washed withwater and extracted with a 1N aqueous solution of sodium hydroxide. Theaqueous layer was washed with ethyl acetate, acidified with 1Nhydrochloric acid and extracted with chloroform. The organic layer wasdried over magnesium sulfate and distilled to remove the solvent. Theobtained residue was chromatographed over silica gel column and elutedwith chloroform to obtain a colorless crystal. This crystal wasrecrystallized from isopropyl ether/hexane to obtain 4.1 g of the titlecompound as a colorless prismatic crystal.

m.p.: 77.5° to 78° C.

·¹ H-NMR(90 MHz, CDCl₃) δ;

0.88 (m, 3H), 1.10˜1.50(m, 2H), 1.60˜1.90(m, 2H(, 2.22(s, 3H), 2.89 and3.05 (ABq, J=16 Hz, 2H), 4.26(t, J=7 Hz, 1H(, 5.86 (s, 2H), 6.52(s, 1H),6.89(s, 1H)

EXAMPLE 16 Sodium [{1-(6-methyl-1,3-benzodioxol-5-yl)butyl}thio]-acetate##STR343##

3.2 g of the title compound was prepared from 3.0 of[{1-(6-methyl-1,3-benzodioxol-5-yl)butyl}thio]-acetic acid as a whitepowder according to the same procedure as that described in Example 8.

m.p.: 233° to 236° C. (decomp.)

·¹ H-NMR(400 MHz, DMSO-d₆) δ;

0.82(t, J=7.3 Hz, 3H), 1.12˜1.27(m, 2H), 1.58˜1.68(m, 1H), 1.70˜1.79 (m,1H), 2.21(s, 3H), 2.67 and 2.71(ABq, J=13.9 Hz, 2H)(, 4.15(dd, J=6.2 Hzand 8.8 Hz, 1H), 5.93 (m, 2H), 6.67(s, 1H), 6.87(s, 1H) ·MS(FAB) m/z ;327(MNa⁻), 305(MH⁻)

EXAMPLE 17 [{(6-Isopropyl-1,3-benzodioxol-5-yl)-methyl}thio]acetic acid##STR344##

A suspension of 3.3 g of 5-chloromethyl-6-isopropyl-1,3-benzodioxole(crude oil) in 10 ml of ethanol was added to a liquid mixture comprising2.1 g of mercaptoacetic acid, 3 g of sodium hydroxide, 25 ml of ethanoland 25 ml of water to carry out the reaction at 80° C. for 40 minutes.The reaction mixture was concentrated, followed by the addition ofwater. The obtained mixture was washed with ethyl acetate. Concentratedhydrochloric acid was added to the mixture to acidify the aqueous layer,followed by the extraction with chloroform. The extract was washed withwater, dried over anhydrous magnesium sulfate and filtered. The filtratewas distilled to remove the solvent. The residue was purified by columnchromatography to obtain 2.45 g of the title compound as a colorlessprismatic crystal.

m.p.: 83° to 84° C.

·¹ H-NMR(90 MHz, CDCl₃) δ;

1.21(d, J=7.2 Hz, 6H), 3.16(s, 2H), 3.18 (sept. J=7.2 Hz, 1H), 3.82(s,2H), 5.90(s, 2H), 6.68(s, 1H), 6.72(s, 1H), 6.6˜8.0 (br, 1H)

EXAMPLE 18 Sodium[{(6-isopropyl-1,3-benzodioxol-5-yl)methyl}thio]-acetate ##STR345##

2.01 g of the title compound was prepared from 2.03 g of[{(6-isopropyl-1,3-benzodioxol-5-yl)methyl}-thio]acetic acid as a whitepowder according to the same procedure as that described in Example 8.

m.p.: 213° to 215° C.

·¹ H-NMR(90 MHz, DMSO-d₆) δ;

1.13(d, J=6.8 Hz, 6H), 2.87(s, 2H), 3.20(sept. J=6.8 Hz, 1H), 3.66(s,2H), 5.87(s, 2H), 6.74(s, 1H), 6.76(s, 1H),

·MS(FAB) m/z ; 313(MNa⁻), 291(MH⁻)

EXAMPLE 19 [{α-(6-Isopropyl-1,3-benzodioxol-5-yl)benzyl]-acetic acid##STR346##

1.2 g of α-(6-isopropyl-1,3-benzodioxol-5-yl)-benzyl alcohol wasdissolved in 10 ml of benzene, followed by the addition of 490 mg ofmercaptoacetic acid and a catalytic amount of p-toluenesulfonic acidmonohydrate. The obtained mixture was heated under reflux for one hourand cooled, followed by the addition of benzene. The mixture was washedwith water, followed by the addition of a 1N aqueous solution of sodiumhydroxide. The alkaline layer was separated, acidified with concentratedhydrochloric acid and extracted with chloroform. The extract was washedwith water, dried over anhydrous magnesium sulfate and filtered. Thefiltrate was distilled to remove the solvent. The residue was purifiedby silica gel column chromatography (hexane/chloroform=3:7) to obtain1.42 g of the title compound as a colorless prismatic crystal.

m.p.: 113.5° to 114.5° C.

·¹ H-NMR(90 MHz, CDCl₃) δ;

1.05(d, J=6.8 Hz, 3H), 1.22(d, J=7.2 Hz, 3H), 3.10(s, 2H), 3.28(m, 1H),5.73(s, 1H), 5.7˜6.0(m, 2H), 6.68(s, 1H), 6.98(s, 1H), 7.05˜7.60(m, 5H)

EXAMPLE 20 Sodium[{α-(6-isopropyl-1,3-benzodioxol-5-yl)benzyl}-thio]-acetate ##STR347##

1.21 g of the title compound was prepared from 1.28 g of[{α-(6-isopropyl-1,3-benzodioxol-5-yl)-benzyl}thio]acetic acid as awhite powder according to the same procedure as that described inExample 8.

m.p.: 199° to 203° C. (decomp.)

·¹ H-NMR(90 MHz, DMSO-d₆) δ;

0.93(d, J=6.8 Hz, 3H), 1.14(d, J=6.8 Hz, 3H), 2.78(s, 2H), 3.0˜3.7(m,1H), 5.68(s, 2H), 5.8˜6.05(m, 2H), 6.76(s, 1H), 6.94(s, 1H),7.05˜7.45(m, 5H) ·MS(FAB) m/z ; 389(MNa⁻)

EXAMPLE 21 [{(6-Benzyl-1,3-benzodioxol-5-yl)methyl}thio]acetic acid##STR348##

0.93 g of the title compound was prepared from 3.5 g of6-benzyl-5-chloromethyl-1,3-benzodioxole as a colorless crystalaccording to the same procedure as that described in Example 17.

m.p.: 99.5° to 100.5° C.

·¹ H-NMR(90 MHz, CDCl₃) δ;

3.10(s, 2H), 3.72(s, 2H), 3.98(s, 2H), 5.86(s, 2H), 6.54(s,1H) 6.76(s,1H), 6.92˜7.35(m, 5H), 8.00˜8.80(br, 1H)

EXAMPLE 22 Sodium[{α-(6-benzyl-1,3-benzodioxol-5-yl)methyl}thio]-acetate ##STR349##

0.95 g of the title compound was prepared from 0.93 g of[{(6-benzyl-1,3-benzodioxol-5-yl)methyl}thio]-acetic acid as a whitepowder according to the same procedure as that described in Example 8.

m.p.: 195° to 205° C.

·¹ H-NMR(400 MHz, DMSO-d₆) δ;

2.86(s, 2H), 3.65(s, 2H), 4.00(s, 2H), 5.94(s, 2H), 6.64(s, 1H), 6.87(s,1H), 7.16˜7.18(m, 3H), 7.25˜7.29(m, 2H)

·MS(FAB) m/z; 339(MH⁻)

EXAMPLE 23 [{2-(6-Isopropyl-1,3-benzodioxol-5-yl)ethyl}thio]-acetic acid##STR350##

2.41 g of 2-(6-isopropyl-1,3-benzodioxol-5-yl)-ethanol was dissolved in50 ml of methylene chloride, followed by the addition of 3.51 g oftriethylamine. 3.31 g of methanesulfonyl chloride was dropwise added tothe obtained mixture at -10° C. The obtained mixture was stirred at -10°C. for 40 minutes, followed by the addition of ice/water. The obtainedmixture was acidified with 1N hydrochloric acid and extracted withmethylene chloride. The extract was washed with water and a saturatedaqueous solution of common salt successively, dried over anhydrousmagnesium sulfate and filtered. The filtrate was concentrated to obtaina methanesulfonate derivative as a crude oil.

A solution of this derivative in 15 ml of ethanol was dropwise added toa mixture comprising 1.60 g of mercaptoacetic acid, 2.3 g of sodiumhydroxide, 15 m of ethanol and 15 ml of water. The obtained mixture wasstirred at 80° to 90° C. for 2 hours and concentrated, followed by theaddition of water. The mixture was washed with ethyl acetate, acidifiedwith concentrated hydrochloric acid and extracted with chloroform. Theextract was washed with water, dried over anhydrous magnesium sulfateand filtered. The filtrate was distilled to remove the solvent. Theresidue was purified by silica gel column chromatography (chloroform) toobtain 2.72 g of the title compound as a colorless prismatic crystal.

m.p.: 75.5° to 76° C.

·¹ H-NMR(90 MHz, CDCl₃) δ;

1.18(d, J=7.2 Hz, 6H), 2.81(bs, 4H), 3.04 (sept, J=7.2 Hz, 1H), 3.24(s,2H), 5.83(s, 2H), 6.56(s, 1H), 6.69(s, 1H), 8.1˜9.0 (br,1H)

EXAMPLE 24 Sodium[{α-(6-isopropyl-1,3-benzodioxol-5-yl)ethyl}-thio]-acetate ##STR351##

2.45 g of the title compound was prepared from 2.236 g of[{2-(6-isopropyl-1,3-benzodioxol-5-yl)-ethyl}thio]acetic acid as a whitepowder according to the same procedure as that described in Example 8.

m.p.: 213° to 215° C.

·¹ H-NMR(90 MHz, DMSO-d₆) δ;

1.12(d, J=6.8 Hz, 6H), 2.45˜2.85(m, 4H), 2.96(s, 2H), 3.04(sept, J=6.8Hz, 1H), 5.86 (s, 2H), 6.66(s, 1H), 6.74(s, 1H),

·MS(FAB) m/z ; 327(MNa⁻), 305(MH⁻)

EXAMPLE 25 [{2-(6-Benzyl-1,3-benzodioxol-5-yl)ethyl}-thio]acetic acid##STR352##

0.93 g of the title compound was prepared from 1.4 g of2-(6-benzyl-1,3-benzodioxol-5-yl)ethanol as a colorless transparent oilaccording to the same procedure as that described in Example 23.

·¹ H-NMR(90 MHz, CDCl₃) δ;

2.44˜2.96(m, 4H), 3.14(s, 2H), 3.90(s, 2H), 5.88(s, 2H), 6.56(s, 1H),6.64(s, 1H), 6.76˜7.36(m, 5H)

EXAMPLE 26 Sodium[{2-(6-benzyl-1,3-benzodioxol-5-yl)ethyl}-thio]-acetate ##STR353##

1.0 g of the title compound was prepared from 0.93 g of[{2-(6-benzyl-1,3-benzodioxol-5-yl)ethyl}-thio]acetic acid as a whitepowder according to the same procedure as that described in Example 8.

m.p.: 185° to 205° C. (decomp.)

·¹ H-NMR(400 MHz, DMSO-d₆) δ;

2.50˜2.54(m, 2H), 2.66˜2.70(m, 2H), 2.89(s, 1H), 3.90(s, 1H), 5.93(s,1H), 6.69(s, 1H), 6.80(s, 1H), 7.12˜7.18(m, 3H), 7.25˜7.28(m, 2H)

·MS(FAB) m/z ; 353(MH⁻)

EXAMPLE 27 [{1-(1,3-Benzodioxol-5-yl)-1-methylethyl}acetamide ##STR354##

500 mg of [}1-(1,3-benzodioxol-5-yl)-1-methylethyl}0thio]acetic acid wasdissolved in 10 ml of benzene, followed by the addition of 0.79 ml ofthionyl chloride. The obtained mixture was stirred at a room temperaturefor 15 hours and distilled to remove the solvent. 3.5 ml oftetrahydrofuran was added to the residue. The obtained mixture wasdropwise added to 30 ml of aqueous ammonia. The mixture was stirred at aroom temperature for 30 minutes and extracted with chloroform. Theextract was washed with a saturated aqueous solution of common salt,dried over anhydrous magnesium sulfate and filtered. The filtrate wasdistilled to remove the solvent. The residue was purified by silica gelcolumn chromatography (ethyl acetate/hexane =4:6) to obtain 240 mg ofthe title compound as a colorless needle.

m.p.: 70° to 71.5° C.

·¹ H-NMR(90 MHz, CDCl₃) δ;

1.67(s, 6H), 2.95 (s, 2H), 5.2˜5.7(bs, 1H), 5.90(s, 2H), 6.2˜6.7(bs,1H), 6.68(d, J=7.9Hz, 1H), 6.87(dd, J=7.9 Hz and 1.8 Hz, 1H), 6.99(d,J=1.8 Hz, 1H)

·MS(FAB) m/z ; 507(2MH⁻), 254(MH⁻)

EXAMPLE 28 N-Methyl-[{1-(1,3-benzodioxol-5-yl)butyl}thio]acetamide##STR355##

2.5 g of the title compound was prepared from 2.7 g of[{1-(1,3-benzodioxol-5-yl)butyl}thio]acetic acid by using a 40% aqueoussolution of methylamine as a colorless oil according to the sameprocedure as that described in Example 27.

·¹ H-NMR(90 MHz, CDCl₃) δ;

0.87(m, 3H), 1.10˜1.50 (m, 2H), 1.67˜1.93(m, 2H), 2.72(d, J=5 Hz, 3H),3.00(s, 2H), 3.62(t, J=7 Hz, 1H), 5.88(s, 2H), 6.50˜6.73(m, 3H), 6.58(m,1H)

·MS m/z; 281(M⁻)

EXAMPLE 29 [{1-(1,3-Benzodioxol-5-yl)butyl}thio]acetamide ##STR356##

1.8 g of the title compound was prepared from 2.7 g of[{1-(1,3-benzodioxol-5-yl)butyl}thio]acetic acid as a white powderaccording to the same procedure as that described in Example 27.

m.p.: 91° to 92° C. ethyl acetate/isopropyl ether)

·¹ H-NMR(90 MHz, CDCl₃) δ;

0.88(m, 3H), 1.11˜1.50(m, 2H), 1.68˜1.94(m, 2H), 2.93 and 3.02 (ABq,J=17 Hz, 2H), 3.68(t, J=7 Hz, 1H), 5.48(brs, 1H), 5.89(s, 2H), 6.45(brs,1H), 6.52˜6.75 (m, 3H)

·MS m/z; 267(M⁻)

EXAMPLE 30 [{1-(6-Methyl-1,3-benzodioxol-5-yl)ethyl}thio]acetamide##STR357##

1.5 g of the title compound was prepared from 2.6 g of[{1-(60methyl-1,30benzodioxol-5-yl)ethyl}-thio]acetic acid as a whitepowder according to the same procedure as that described in Example 27.

m.p.: 121° to 122° C.

·¹ H-NMR(90 MHz, CDCl₃) δ;

1.53(d, J=7 Hz, 3H), 2.22(s, 3H), 2.93 and 3.05(ABq, J=16 Hz, 2H),4.21(q, J=7 Hz, 1H), 5.68(brs, 1H), 5.85(s, 2H), 6.50(brs, 1H), 6.53(s,1H), 6.87(s, 1H)

·MS m/z; 253(M⁻)

EXAMPLE 31 [{2-(6-Ethyl-1,3-benzodioxol-5-yl)ethyl}thio]acetamide##STR358##

1.1 g of the title compound was prepared from 2.0 g of[{2-(6-ethyl-1,3-0benzodioxol-5-yl)ethyl}thio]-acetic acid as acolorless crystal according to the same procedure as that described inExample 27.

m.p.: 98° to 99° C.

·¹ H-NMR(400 MHz, DMSO-d₆) δ;

1.10(t, J=7.5 Hz, 3H), 2.49˜2.54 (m, 2H), 2.68˜2.77(m, 4H), 3.11(s, 2H),5.92(s, 2H), 6.73(s, 1H), 6.76(s, 1H), 7.01(s, 1H), 7.43(s, 1H)

·MS(FD) m/z; 267(MH⁻)

EXAMPLE 32N,N-dimethyl-[{1-(6-methyl-1,3-benzodioxol-5-yl)-ethyl}thio]acetamide##STR359##

2.6 g of [{1-(6-methyl-1,3-benzodioxol-5-yl)-ethyl{thio] acetic acid wasdissolved in 20 ml of benzene, followed by the addition of 1.4 ml ofthionyl chloride. The obtained mixture was heated under reflux for onehour and concentrated in a vacuum to obtain an acid chloride derivativeas a brown oil.

Separately, 2.0 g of sodium hydroxide was dissolved in 10 ml of water toobtain a solution. Dimethylamine hydrochloride was added to the solutionunder cooling with ice. The above derivative was dropwise added to theobtained mixture. The obtained mixture was stirred at a room temperatureovernight, followed by the addition of water. The mixture was extractedwith chloroform. The organic layer was dried over magnesium sulfate anddistilled to remove the solvent. The residue was purified by silica gelcolumn chromatography (ethyl acetate/hexane=5:95) to obtain 2.1 g of thetitle compound as a colorless oil.

·¹ H-NMR(90 MHz, CDCl₃) δ;

1.53(d, J=7 Hz, 3H), 2.27(s, 3H), 2.90(s, 3H), 2.95(s, 3H), 3.08 and3.19(ABq, J=14 Hz, 2H), 4.34(q, J=7 Hz, 1H), 5.85(s, 2H), 6.55(s, 1H),6.94(s, 1H)

·MS m/z; 281(M⁻)

EXAMPLE 33N,N-Diethyl-[{2-(6-ethyl-1,3-benzodioxol-5-yl)ethyl}-thio]acetamide##STR360##

2.1 g of the title compound was prepared from 2.0 g of[{2-(6-ethyl-1,3-benzodioxol-5-yl)ethyl}thio]-acetic acid by using 2.7 gof diethylamine as a pale yellow oil according to the same procedure asthat described in Example 32.

·¹ H-NMR(400 MHz, DMSO-d₆) δ;

1.01(t, J=7.1 Hz, 3H), 1.10(t, J=7.5 Hz, 3H), 1.12(t, J=7.1 Hz, 3H),2.52(q, J=7.3 Hz, 2H), 2.68˜2.78(m, 4H), 3.25(q, J=7.0 Hz, 2H), 3.33(q,J=7.0 Hz, 2H), 3.39(s, 2H), 5.92(s, 2H), 6.72(s, 1H), 6.76(s, 1H)

·MS (FD) m/z; 323(M⁻)

EXAMPLE 34N-[2-[{(1,3-Benzodioxol-5-yl)butyl}thio]-1-oxoethyl]-aminoacetic acid##STR361##

1.4 g of [{(1,3-benzodioxol-5-yl)butyl}thio]acetic acid was dissolved in10 ml of benzene, followed by the addition of 0.8 ml of thionylchloride. The obtained mixture was heated under reflux for 1.5 hours andconcentrated in a vacuum to obtain a residue. Separately, 0.43 g ofsodium hydroxide was dissolved in 4 ml of water, followed by theaddition of 0.8 g of glycine to obtain a mixture. The above residue wasdissolved in a small amount of tetrahydrofuran to obtain a solution.This solution was dropwise added to the above mixture under cooling withice/water. The obtained mixture was stirred for 30 minutes, followed bythe addition of water. The mixture was acidified with concentratedhydrochloric acid and extracted with chloroform. The organic layer wasdried over magnesium sulfate and distilled to remove the solvent. Thus,a brown oil was obtained. This oil was crystallized from isopropyl etherto obtain 1.0 g of the title compound as a light brown crystal.

m.p.: 95° to 96° C.

·¹ H-NMR(90 MHz, CDCl₃) δ;

0.87(m, 3H), 1.10˜1.50(m, 2H), 1.68˜1.93(m, 2H), 3.02 and 3.07(ABq, J=17Hz, 2H), 3.76(t, J=7 Hz, 1H), 3.99(t, J=5 Hz, 2H), 5.88(s, 2H),6.68˜6.75(m, 3H), 7.16(m, 1H), 7.49(brs, 1H)

EXAMPLE 35 SodiumN-[2-[{(1,3-benzodioxol-5-yl)butyl}thio]-1-oxoethyl]aminoacetate##STR362##

0.5 g of the title compound was prepared from 0.5 g ofN-[2-{(1,3-benzodioxol-5-yl)butyl}thio]-1-oxoethyl]aminoacetic acid as awhite powder according to the same procedure as that described inExample 8.

m.p.: 264° to 270° C. (decomp.)

·¹ H-NMR(400 MHz, DMSO-d₆) δ;

0.82(t, J=7.3 Hz, 3H), 1.11˜1.28(m, 2H), 1.67˜1.80(m, 2H), 2.80 and 3.03(ABq, J=15.0 Hz, 2H), 3.25(d, J=4.0 Hz, 2H), 3.91(dd, J=6.6 Hz and 8.8Hz, 1H), 6.80(d, J=7.7 Hz, 1H), 6.87(d, J=1.5 Hz, 1H), 7.44(brs, 1H)

·MS(FAB) m/z; 370(MNa⁻), 348 (MH⁻)

What is claimed is:
 1. A benzodioxole derivative having the formula (I)or a pharmacologically acceptable salt thereof: ##STR363## wherein T, U,V and W are defined according to group (i) or (ii): (i) T is hydrogen, Uis hydrogen, V is hydrogen, and W is --(CH₂)₂ --X--Rwherein X representsa group of the formula: ##STR364## and R represents: (1) a group of theformula (CH₂)_(n) --COOR¹ in which n represents an integer of 1 to 5 andR¹ represents a hydrogen atom or a lower alkyl group, (2) a group of theformula --(CH₂)_(n) --CONR³ R⁴ in which n represents an integer of 1 to5 and R³ and R⁴, which may be the same or different, each represents ahydrogen atom, a lower alkyl group or a carboxymethyl group; (ii) T andU, which may be the same or different, each represents a hydrogen atomor a lower alkyl group, V represents a hydrogen atom, a lower alkylgroup, or a group of the formula --(CH₂)₂ COOH in which z represents aninteger of 1 to 3, and W represents a group of the formula:

    --CH.sub.2 --CR.sup.5 R.sup.6 --A--Z

wherein R⁴ and R⁶ may be the same or different and each represents ahydrogen atom or a lower alkyl group, X represents ##STR365## and Arepresents CR⁷ R⁸ -COOH in which R⁷ and R⁸ may be the same or differentand each represents a hydrogen atom or a lower alkyl group.
 2. Abenzodioxole derivative as claimed in claim 1, wherein the formula (I)is defined with the group (i) or a pharmacologically acceptable saltthereof.
 3. A benzodioxole derivative as claimed in claim 1, wherein theformula (I) is defined with the group (i) and X is --S--, or apharmacologically acceptable salt thereof.
 4. A benzodioxole derivativeas claimed in claim 1, wherein the formula (I) is defined with the group(i), X is --S-- and R is (CH₂)_(n) -COOR¹, n being 1 to 5, R¹ beinghydrogen or a lower alkyl, or a pharmacologically acceptable saltthereof.
 5. A benzodioxole derivative as claimed in claim 1, wherein theformula is defined with the group (i) X is --S-- and R is --CH₂ --COOH,or a pharmacologically acceptable salt thereof.
 6. A benzodioxolederivative as claimed in claim 1, wherein the formula (I) is definedwith the group (ii) or a pharmacologically acceptable salt thereof.
 7. Abenzodioxole derivative as claimed in claim 1, wherein thepharmacologically acceptable salt is sodium salt.
 8. A pharmaceuticalcomposition comprising a benzodioxole derivative as claimed in claim 1or a phramacologically acceptable salt thereof and a pharmacologicallyacceptable carrier.